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Journal articles on the topic 'CYP 3A4'

Author: Grafiati

Published: 4 June 2021

Last updated: 12 February 2022

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BAUNE, B., J. P. FLINOIS, V. FURLAN, et al. "Halofantrine Metabolism in Microsomes in Man: Major Role of CYP 3A4 and CYP 3A5." Journal of Pharmacy and Pharmacology 51, no. 4 (1999): 419–26. http://dx.doi.org/10.1211/0022357991772628.

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Elsherbiny, Marwa E., Ayman O. S. El-Kadi, and Dion R. Brocks. "The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole." Journal of Pharmacy & Pharmaceutical Sciences 11, no. 1 (2008): 147. http://dx.doi.org/10.18433/j3sg66.

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PURPOSE. To evaluate the metabolism of amiodarone (AM) to desethylamiodarone (DEA) by selected human and rat cytochrome P450, and the inhibitory effect of ketoconazole (KTZ). METHODS. Some important CYP isoenzymes (rat CYP1A1, 1A2, 2C6, 2C11, 2D1, 2D2, and 3A1 and human CYP1A1, 1A2, 2D6 and 3A4) were spiked with various concentrations of AM to determine the relative kinetic parameters for formation of DEA in the presence and absence of various concentrations of KTZ. RESULTS. The formation of DEA was observed when AM was exposed to each of the CYP tested, although the rates were varied. Human CYP1A1 followed by 3A4 had the highest intrinsic clearance (CLint) for DEA formation whereas in rat, CYP2D1 followed by CYP2C11 had the highest CLint. Human and rat CYP1A2 seemed to have the lowest CLint. At high concentrations of AM and KTZ, near those expected in vivo, significant inhibition of all isoforms except for rat CYP1A2 was observed. At lower concentration ranges of both drugs, the inhibitory constant was determined. At these levels, KTZ was found to potently inhibit human CYP1A1 and 3A4 and rat 2D2 and 1A1. CONCLUSION. Human CYP1A1 and 3A4 and rat CYP2D1 and 2C11 were most efficient in converting AM to DEA. For DEA formation, the in vivo administration of KTZ could inhibit other CYP isoforms besides CYP3A in human and rat.

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Oda, Kazuaki, Yukio Tamai, Yuki Yamaguchi, et al. "Synthetic Models Related to Furanocoumarin-CYP 3A4 Interactions. Synthesis of Furanocoumarin Derivatives as Potent Inhibitors of CYP 3A4." HETEROCYCLES 71, no. 1 (2007): 1. http://dx.doi.org/10.3987/com-06-10873.

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Bossaer, John B., and Kanishka Chakraborty. "Drug interaction between idelalisib and diazepam resulting in altered mental status and respiratory failure." Journal of Oncology Pharmacy Practice 23, no. 6 (2016): 470–72. http://dx.doi.org/10.1177/1078155216653705.

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In recent years, several new oral anticancer drugs have been approved, many via an accelerated approval process. These new agents have the potential for drug interactions, but lack of familiarity with these drugs by clinicians may increase the risk for drug interactions. We describe an interaction between the new anticancer agent idelalisib (CYP 3A4 inhibitor) and diazepam (CYP 3A4 substrate) that resulted in altered mental status and type II respiratory failure resulting in hospitalization. After discontinuation of both agents, the patient recovered quickly. Idelalisib was reinitiated after discharge. Lorazepam was substituted for diazepam since it is not metabolized via CYP 3A4. Both agents were tolerated well thereafter. This interaction was only flagged by two of four commonly used drug interaction databases. Clinicians should exercise caution with initiating new oral anticancer agents and consider the potential for drug interactions without solely relying on drug interaction databases.

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Bell, Leslie, Shari Bickford, Phong Hung Nguyen, et al. "Evaluation of Fluorescence- and Mass Spectrometry—Based CYP Inhibition Assays for Use in Drug Discovery." Journal of Biomolecular Screening 13, no. 5 (2008): 343–53. http://dx.doi.org/10.1177/1087057108317480.

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The potential for metabolism-related drug-drug interactions by new chemical entities is assessed by monitoring the impact of these compounds on cytochrome P450 (CYP) activity using well-characterized CYP substrates. The conventional gold standard approach for in vitro evaluation of CYP inhibitory potential uses pooled human liver microsomes (HLM) in conjunction with prototypical drug substrates, often quantified by LC-MS/MS. However, fluorescent CYP inhibition assays, which use recombinantly expressed CYPs and fluorogenic probe substrates, have been employed in early drug discovery to provide low-cost, high-throughput assessment of new chemical entities. Despite its greatly enhanced throughput, this approach has been met with mixed success in predicting the data obtained with the conventional gold standard approach (HLM+LC-MS). The authors find that the predictivity of fluorogenic assays for the major CYP isoforms 3A4 and 2D6 may depend on the quality of the test compounds. Although the structurally more optimized marketed drugs yielded acceptable correlations between the fluorogenic and HLM+LC-MS/MS assays for CYPs 3A4, 2D6, and 2C9 ( r 2 = 0.5-0.7; p < 0.005), preoptimization, early discovery compounds yielded poorer correlations ( r 2 ≤ 0.2) for 2 of these major isoforms, CYPs 3A4 and 2D6. Potential reasons for the observed differences are discussed. ( Journal of Biomolecular Screening 2008;343-353)

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Xue, Yuhan, Junhao Li, Zengrui Wu, Guixia Liu, Yun Tang, and Weihua Li. "Computational insights into the different catalytic activities of CYP 3A4 and CYP 3A5 toward schisantherin E." Chemical Biology & Drug Design 93, no. 5 (2019): 854–64. http://dx.doi.org/10.1111/cbdd.13475.

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Song, Xiaoli, Gang Dong, and Yun Zhou. "In vitro Inhibitory Effects of Isofraxidin on Human Liver Cytochrome P450 Enzymes." Pharmacology 103, no. 3-4 (2018): 120–27. http://dx.doi.org/10.1159/000495212.

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Isofraxidin is a Coumarin compound widely distributed in plants, such as the Umbelliferae or Chloranthaceae, and it possesses numerous pharmacological activities. However, whether isofraxidin affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. In this study, the inhibitory effects of isofraxidin on the 8 human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes. The results showed that isofraxidin inhibited the activity of CYP1A2, 3A4, and 2E1, with IC50 values of 23.01, 15.49, and 15.98 µmol/L, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that isofraxidin was not only a noncompetitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP1A2 and 2E1, with Ki values of 7.91, 10.14, and 9.30 µmol/L, respectively. In addition, isofraxidin is a time-dependent inhibitor for CYP3A4 with Kinact/KI value of 0.047/12.33 µmol/L–1min–1. The in vitro studies of isofraxidin with CYP isoforms indicate that isofraxidin has the potential to cause pharmacokinetic drug interactions with other coadministered drugs metabolized by CYP1A2, 3A4, and 2E1. Further clinical studies are needed to evaluate the significance of this interaction.

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Wang, Lei, Xiuju Ma, Jing Wang, and Chang Li. "In vitro Inhibitory Effects of Cynaroside on Human Liver Cytochrome P450 Enzymes." Pharmacology 104, no. 5-6 (2019): 296–302. http://dx.doi.org/10.1159/000502172.

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Introduction: Cynaroside is a biological component isolated from Lonicera japonica Thunb, and it possesses numerous pharmacological activities. However, whether cynaroside affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. The purpose of this study was to investigate the effects of cynaroside on 8 major CYP isoforms in human liver microsomes (HLMs). Methods: In this study, the inhibitory effects of cynaroside on the 8 human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using HLMs. Results: The results showed that cynaroside inhibited the activity of CYP1A2, 3A4, and 2C9, with IC50 values of 21.74, 15.88, and 16.58 μmol/L, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that cynaroside was not only a noncompetitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP1A2 and 2C9, with Ki values of 7.33, 11.60, and 8.09 μmol/L, respectively. In addition, cynaroside is a time-dependent inhibitor for CYP3A4 with Kinact/KI value of 0.049/11.62 μmol/L–1min–1. Conclusion: The in vitro studies of cynaroside with CYP isoforms indicate that cynaroside has the potential to cause pharmacokinetic drug interactions with other coadministered drugs metabolized by CYP1A2, 3A4, and 2C9. Further clinical studies are needed to evaluate the significance of this interaction.

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Trapnell, C. B., C. Jamis-Dow, R. W. Klecker, and J. M. Collins. "Metabolism of rifabutin and its 25-desacetyl metabolite, LM565, by human liver microsomes and recombinant human cytochrome P-450 3A4: relevance to clinical interaction with fluconazole." Antimicrobial Agents and Chemotherapy 41, no. 5 (1997): 924–26. http://dx.doi.org/10.1128/aac.41.5.924.

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Rifabutin and fluconazole are often given concomitantly as therapy to prevent opportunistic infections in individuals infected with the human immunodeficiency virus. Recent reports have shown increased levels of rifabutin and its 25-desacetyl metabolite, LM565, in plasma when rifabutin is administered with fluconazole. Since fluconazole is known to inhibit microsomal enzymes, this study was undertaken to determine if this rifabutin-fluconazole interaction was due to an inhibition of human hepatic enzymes. The metabolism of both rifabutin and LM565 was evaluated in human liver microsomes and recombinant human cytochrome P-450 (CYP) 3A4 in the presence of fluconazole and other probe drugs known to inhibit CYP groups 1A2, 2C9, 2D6, 2E1, and 3A. The concentrations of rifabutin (1 microg/ml), LM565 (1 microg/ml), and fluconazole (10 and 100 microg/ml) used were equal to those observed in plasma after the administration of rifabutin and fluconazole at clinically relevant doses. High-performance liquid chromatography was used to assess the metabolism of rifabutin and LM565. Rifabutin was readily metabolized to LM565 by human microsomes, but the reaction was independent of NADPH and was not affected by the P-450 inhibitors. No rifabutin metabolism by recombinant CYP 3A4 was found to occur. LM565 was also metabolized by human microsomes to two products, but metabolism was dependent on NADPH and was affected by certain P-450 inhibitors. In addition, LM565 was readily metabolized by the recombinant CYP 3A4 to the same two products found with its metabolism by human microsomes. Therefore, rifabutin is metabolized by human microsomes but not via cytochrome P-450 enzymes, whereas LM565 is metabolized by CYP 3A4.

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Zhang, Jinhui, Li Li, Suni Tang, et al. "Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica." American Journal of Chinese Medicine 43, no. 06 (2015): 1211–30. http://dx.doi.org/10.1142/s0192415x1550069x.

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We have shown that the in vitro hepatic microsomal metabolism of pyranocoumarin compound decursinol angelate (DA) to decursinol (DOH) exclusively requires cytochrome P450 (CYP) enzymes, whereas the conversion of its isomer decursin (D) to DOH can be mediated by CYP and esterase(s). To provide insight into specific isoforms involved, here we show with recombinant human CYP that 2C19 was the most active at metabolizing D and DA in vitro followed by 3A4. With carboxylesterases (CES), D was hydrolyzed by CES2 but not CES1, and DA was resistant to both CES1 and CES2. In human liver microsomal (HLM) preparation, the general CYP inhibitor 1-aminobenzotriazole (ABT) and respective competitive inhibitors for 2C19 and 3A4, (+)-N-3-benzylnirvanol (NBN) and ketoconazole substantially retarded the metabolism of DA and, to a lesser extent, of D. In healthy human subjects from a single-dose pharmacokinetic (PK) study, 2C19 extensive metabolizer genotype (2C19*17 allele) tended to have less plasma DA AUC0-48h and poor metabolizer genotype (2C19*2 allele) tended to have greater DA AUC0-48h. In mice given a single dose of D/DA, pretreatment with ABT boosted the plasma and prostate levels of D and DA by more than an order of magnitude. Taken together, our findings suggest that CYP isoforms 2C19 and 3A4 may play a crucial role in the first pass liver metabolism of DA and, to a lesser extent, that of D in humans. Pharmacogenetics with respect to CYP genotypes and interactions among CYP inhibitor drugs and D/DA should therefore be considered in designing future translation studies of DA and/or D.

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&NA;. "Hypericum may reduce efficacy of CYP 3A4 substrates." Reactions Weekly &NA;, no. 970 (2003): 5. http://dx.doi.org/10.2165/00128415-200309700-00011.

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&NA;. "Hypericum may reduce efficacy of CYP 3A4 substrates." Inpharma Weekly &NA;, no. 1406 (2003): 21. http://dx.doi.org/10.2165/00128413-200314060-00046.

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Muntafiah, Laeli, Bani Adlina Shabrina, Dwi Sulistyowati, Murah Riski Novi Asshagab, and Riris Istighfari Jenie. "Anti-Aging Activity Of Cucurbita moschata Ethanolic Extract Towards NIH3T3 Fibroblast Cells Induced By Doxorubicin." Indonesian Journal of Cancer Chemoprevention 7, no. 2 (2017): 49. http://dx.doi.org/10.14499/indonesianjcanchemoprev7iss2pp49-53.

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Degenerative disease caused by decreasing organ function in old people has become the biggest death cause in the world. This aging process marked by senescence activity. An anti-aging agent from the medicinal plant has high potency to be developed, such as pumpkin seed (Cucurbita moschata) which contain tocopherol as antioxidant. The aim of this study is to investigate the anti-aging effect of pumpkin seed extract (PSE) on NIH 3T3 fibroblast normal cell induced by doxorubicin. This anti-aging effect was observed using MTT assay continued by SA- βgal (Senescence-Associated Beta-Galactosidase) activity detection test. The stability of molecular interaction between tocopherol and doxorubicin to CYP 3A4 as the oxidase enzyme was conducted using molecular docking. Based on in vitro test, PSE is not cytotoxic to NIH 3T3. PSE at the dose of 100,200,400, and 800 μg/mL decreased % cell senescence by 2,77; 4,5; 6; and 18 times respectively. Meanwhile, in silico test indicated that tocopherol (-107,409) has a higher interaction to CYP 3A4 compared to doxorubicin (-70,52). Both compounds have a similar binding site in Leu 364; Phe 435; Pro 434; Cys 442; Ile 369; Thr 309; dan Ala 305. The overall result of this study showed that PSE has anti-aging effect by decreasing SA- βgal activity. This anti-aging activity possibly due to the interaction between tocopherol to CYP 3A4 based on molecular docking.Keywords: anti-aging, Cucurbita moschata, tocopherol, SA-βgal, molecular docking

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Kuznetsova, E. Yu, T. A. Sokolova-popova, A. V. Shulmin, et al. "THE EFFECT OF POLYMORPHIC GENES OF DETOXIFICATION SYSTEMS (CYP 1A1, CYP 1A2, CYP 2C9 (*2), CYP 2C9(*3), CYP 2C19, CYP 2E1(PSTI/RSAI), CYP 2E1(TAGI), CYP 3A4) ON THE THERAPEUTIC EFFICACY OF TREATMENT OF PATIENTS WITH LYMPHOPROLIFERATIVE DISEASES." Современные проблемы науки и образования (Modern Problems of Science and Education), no. 6 2019 (2019): 49. http://dx.doi.org/10.17513/spno.29316.

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Duman, Amanda K., and Patricia Pecora Fulco. "Adrenal Insufficiency With Voriconazole and Inhaled/Intranasal Corticosteroids: Case Report and Systematic Review." Journal of Pharmacy Practice 30, no. 4 (2016): 459–63. http://dx.doi.org/10.1177/0897190016646510.

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Strong cytochrome P450 (CYP) 3A4 inhibitors may induce Cushing syndrome and subsequent adrenal insufficiency when administered concurrently with corticosteroids. This drug–drug interaction has been well described with HIV protease inhibitors. A similar drug–drug interaction with corticosteroids and other strong CYP 3A4 inhibitors (antifungals [imidazoles]) has recently been reported but remains less well known. To our knowledge, we report the first case of probable drug-induced Cushing syndrome with subsequent adrenal insufficiency as a result of concomitant oral voriconazole with intranasal mometasone and inhaled fluticasone administration as well as a review of the current literature supporting this drug–drug interaction.

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Chougnet, Antoinette, Catherine Stoessel, and Wolf-D. Woggon. "Design and synthesis of a new fluorescent probe for cytochrome P450 3A4 (CYP 3A4)." Bioorganic & Medicinal Chemistry Letters 13, no. 21 (2003): 3643–45. http://dx.doi.org/10.1016/j.bmcl.2003.08.027.

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Nguyen, San, Huang Huang, Brian C. Foster, et al. "Antimicrobial and P450 Inhibitory Properties of Common Functional Foods." Journal of Pharmacy & Pharmaceutical Sciences 17, no. 2 (2014): 254. http://dx.doi.org/10.18433/j3p599.

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PURPOSE: To study the effect of functional foods on human cytochrome P450 (CYP) and the gut bacterial microflora that may potentially affect drug metabolism and ultimately affect human health and wellness. METHODS: This study examined a variety of food plants from the Apiaceae, Fabaceae, and Lamiaceae families for their inhibitory potential on cytochrome 2D6-, 3A4-, 3A5-, and 3A7-mediated metabolism. The antimicrobial effects of these samples were also investigated with 7 selected bacterial surrogate species to determine potential effects on the gut microflora. RESULTS: The highest CYP inhibitory activities, based upon visual examination, were observed from extracts of celery seed, cumin, fennel seed, basil, oregano, and rosemary belonging to the Apiaceae and Lamiaceae families, respectively. Likewise, the strongest antimicrobial activities were also observed in the Apiaceae and Lamiaceae. No significant antimicrobial and CYP inhibition was observed in the Fabaceae extracts. CONCLUSION: Results demonstrated the possible risk of food-drug interactions from spice and herb plants may affect drug disposition and safety. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Al-Dosari, Mohammed, Guisheng Zhang, Joseph E. Knapp, and Dexi Liu. "Direct Assessment of Promoter Activity of Human Cytochrome P450 Genes Using Optimized Transfection in Vitro and in Vivo." Bioscience Reports 26, no. 3 (2006): 217–29. http://dx.doi.org/10.1007/s10540-006-9017-9.

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Although transcription regulation of human cytochrome P450 enzymes (CYP) is known to play an important role in drug metabolism and homeostasis, factors influencing the expression of various CYP genes in humans remain largely undefined. We used three cell lines and CD-1 mice to assess the activity of genomic promoter sequences of human CYP2D6, 1A2, 3A4, 2C9, 2C18, and 2E1 genes. CYP promoter sequences were amplified by PCR using human liver genomic DNA as the template and cloned into pGL3-Basic vectors that contain a luciferase reporter gene but lack promoter or enhancer sequences. Each plasmid construct was transfected into cells in vitro using polyethylenimine (PEI) as the transfection reagent and into mice using the recently developed hydrodynamics-based procedure. Relative promoter strength was determined by the level of luciferase expression in transfected cells. All six human CYP promoters are active in driving reporter gene expression in cultured hepatic HepG2 cells and non-hepatic cells such as human embryonic kidney fibroblasts (293 cells) and murine melanoma cells (BL-16) as well as cells in intact mouse liver, lung, heart, kidney and spleen. The order of strength among CYP promoters examined was found to be 2D6 > 1A2 > 3A4 > 2C9 > 2C18 > 2E1.

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. "interacties, cisaprideInteractie claritromycine, CYP2C19 claritromycine, CYP3A4claritromycine ’ omeprazol, CYP3A4 omeprazol, CYP2C19omeprazol via CYP2C19, omeprazol CYP2C19, claritromycineCYP2C19 en CYP 3A4, omeprazol CYP 3A4, claritromycineCYP3A4." Medisch-Farmaceutische Mededelingen 38, no. 12 (2000): 253–54. http://dx.doi.org/10.1007/bf03057642.

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Girennavar, Basavaraj, Shibu M. Poulose, Guddadarangavvanahally K. Jayaprakasha, Narayan G. Bhat, and Bhimanagouda S. Patil. "Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes." Bioorganic & Medicinal Chemistry 14, no. 8 (2006): 2606–12. http://dx.doi.org/10.1016/j.bmc.2005.11.039.

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Pang, Xiaocong, Baoyue Zhang, Guangyan Mu, et al. "Screening of cytochrome P450 3A4 inhibitors via in silico and in vitro approaches." RSC Advances 8, no. 61 (2018): 34783–92. http://dx.doi.org/10.1039/c8ra06311g.

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Cytochrome P450 3A4 (CYP3A4) is an important member of the CYP family and responsible for metabolizing a broad range of drugs. It is necessary to establish virtual screening models for predicting CYP3A4 inhibitors.

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Paul, Sean, Brian K. Cooke, and Mathew Nguyen. "Glossopharyngeal Dystonia Secondary to a Lurasidone-Fluoxetine CYP-3A4 Interaction." Case Reports in Psychiatry 2013 (2013): 1–3. http://dx.doi.org/10.1155/2013/136194.

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Acute dystonic reactions are becoming much less prevalent in clinical practice due to the use of newer antipsychotics. Drug-drug interactions, patient characteristics, and environmental and genetic factors all contribute to the rate of occurrence of acute dystonia with second generation agents. In this case, we report a glossopharyngeal dystonia secondary to a lurasidone-fluoxetine CYP-3A4 interaction to highlight the importance of maintaining an index of suspicion for laryngeal dystonia, a potentially fatal dystonia.

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Shabrina, Bani Adlina, Juang Juansa, Nindya Budiana Putri, Rohmad Yudi Utomo, and Retno Murwanti. "Antigenotoxicity Activity of Papaya (Carica papaya L.) Leaf Ethanolic Extract on Swiss Mice Induced Cyclophosphamide through Mammalian In Vivo Micronucleus Test." Indonesian Journal of Cancer Chemoprevention 7, no. 1 (2017): 31. http://dx.doi.org/10.14499/indonesianjcanchemoprev7iss1pp31-37.

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Cyclophosphamide (CPA) is an effective chemotherapeutic agent, but has side effect, causing DNA damage (genotoxic). Papaya leaf (Carica papaya L.) is known has flavonoid compound, quercetin. Quercetin is known has DNA protecting effect (antigenotoxic effect) by metabolism modulation. Thus, the aim of this research is to investigate the antigenotoxic effect of ethanolic extract of papaya (Carica papaya L.) leaf (EEPL) on CPA induced mice. The antigenotoxic effect was evaluated by mammalian in vivo micronucleus test. EEPL was orally administered as single treatment at dose 1000 mg/kgBW and in combination with CPA 50 mg/kgBW at dose 250 mg/kgBW; 500 mg/kgBW; and 1000 mg/kgBW. Molecular docking using PLANTS on CYP 3A4 was performed to explore the antigenotoxic effect mechanism. The three different combination dose of EEPL with CPA significantly (P<0.05) decreased the amount of micronucleated polychromatic erytrhocyte (MNPCE)/1000 polychromatic erythrocyte (PCE) and also increased % PCE/(PCE+normochromatic erythrocyte (NCE)), compared with single dose of CPA. Nevertheless, the antigenotoxic effect wasn’t significant compared with each combination dose. The docking score result showed quercetin (-82,41) has more potent interaction to CYP 3A4 than cyclophosphamide (-70,16) and both of them has similar active site at amino acid residue Ile 369 and Thr 309. The results obtained indicated that EEPL at dose 250 mg/KgBB is the optimal dose as antigenotoxic agent by interaction between quercetin with CYP 3A4 based on molecular docking.Keywords: antigenotoxic, Carica papaya L., MNPCE, in vivo

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Siwek, Marcin, Anna J. Krupa, and Anna Wasik. "Lurasidone – pharmacodynamic and pharmacokinetic properties, clinical potential and interaction risk." Pharmacotherapy in Psychiatry and Neurology 36, no. 2 (2020): 117–34. http://dx.doi.org/10.33450/10.33450/fpn.2020.06.002.

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Lurasidone is a novel second-generation antipsychotic approved for the treatment of schizophrenia and bipolar depression in adults. It displays high affinity for D2 and 5-HT2A and 5-HT7 receptors, moderate affinity for 5-HT1A and α2C-noradrenergic receptors, and negligible affinity for histamine H1 and muscarinic M1 receptors. It acts as potent D2, 5-HT2A and 5-HT7 antagonist and partial 5-HT1A agonist. Lurasidone taken orally is rapidly absorbed with the time to maximum concentration of 1-3 hours. Lurasidone should be taken with food (at least 350 kcal) due to limited absorption. The mean elimination half-life of lurasidone is 18.1–25.5 hours for doses 20–80 mg/day and 28.8–37.4 hours for doses of 120–160 mg/day. Steady-state is reached within 7 days. The drug is metabolised via CYP 3A4 and excreted mainly in faeces (67–80%) and with urine (about 8–19%). The use of lurasidone with strong inhibitors or inducers of CYP 3A4 (e.g. ketoconazole, erythromycin, or carbamazepine, respectively) is contraindicated. In the case of combined treatment of lurasidone and moderate inhibitors of CYP 3A4, the dose of lurasidone should be decreased to 40 mg/day. Lurasidone is an inhibitor of P-glycoprotein and could increase the level of digoxin and potentate the side effects risk of this drug. Pomelo, grapefruit, or a large amount of oranges should be avoided in the diet during treatment with lurasidone. Pharmacodynamic properties of lurasidone underlie its antipsychotic, antidepressant, precognitive, and sleep-awake rhythm normalising activity.

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Forster, Janice, Jessica Duis, and Merlin G. Butler. "Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome." Genes 12, no. 2 (2021): 152. http://dx.doi.org/10.3390/genes12020152.

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Prader-Willi syndrome (PWS) is associated with co-morbid psychiatric symptoms (disruptive behavior, anxiety, mood disorders, and psychosis) often requiring psychotropic medications. In this clinical case series of 35 patients with PWS, pharmacogenetic testing was obtained to determine allele frequencies predicting variations in activity of cytochrome (CYP) P450 drug metabolizing enzymes 2D6, 2B6, 2C19, 2C9, 3A4, and 1A2. Results were deidentified, collated, and analyzed by PWS genetic subtype: 14 deletion (DEL), 16 maternal uniparental disomy (UPD) and 5 DNA-methylation positive unspecified molecular subtype (PWS Unspec). Literature review informed comparative population frequencies of CYP polymorphisms, phenotypes, and substrate specificity. Among the total PWS cohort, extensive metabolizer (EM) activity prevailed across all cytochromes except CYP1A2, which showed greater ultra-rapid metabolizer (UM) status (p < 0.05), especially among UPD. Among PWS genetic subtypes, there were statistically significant differences in metabolizing status for cytochromes 2D6, 2C19, 2C9, 3A4 and 1A2 acting on substrates such as fluoxetine, risperidone, sertraline, modafinil, aripiprazole, citalopram, and escitalopram. Gonadal steroid therapy may further impact metabolism of 2C19, 2C9, 3A4 and 1A2 substrates. The status of growth hormone treatment may affect CYP3A4 activity with gender specificity. Pharmacogenetic testing together with PWS genetic subtyping may inform psychotropic medication dosing parameters and risk for adverse events.

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BARNAS, C., M. KRECICSHEPARD, J. SLIMKO, and J. SCHWARTZ. "Comparison of clearance of three CYP 3A4/5 substrates in patients." Clinical Pharmacology & Therapeutics 65, no. 2 (1999): 191. http://dx.doi.org/10.1016/s0009-9236(99)80297-5.

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. "Invloed van grapefruitsap op het simvastatine, CYP 3A4 simvastatine, grapefruitsapsimvastatine-metabolisme." Medisch-Farmaceutische Mededelingen 38, no. 1 (2000): 15. http://dx.doi.org/10.1007/bf03057465.

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Totah, Rheem A., Pamela Sheffels, Toni Roberts, Dale Whittington, Kenneth Thummel, and Evan D. Kharasch. "Role of CYP2B6 in Stereoselective Human Methadone Metabolism." Anesthesiology 108, no. 3 (2008): 363–74. http://dx.doi.org/10.1097/aln.0b013e3181642938.

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Background Metabolism and clearance of racemic methadone are stereoselective and highly variable, yet the mechanism remains largely unknown. Initial in vitro studies attributed methadone metabolism to cytochrome P4503A4 (CYP3A4). CYP3A4 was also assumed responsible for methadone clearance in vivo. Nevertheless, recent clinical data do not support a primary role for CYP3A4 and suggest that CYP2B6 may mediate methadone clearance. Expressed CYP2B6 and also CYP2C19 N-demethylate methadone in vitro. This investigation tested the hypothesis that CYPs 2B6, 3A4, and/or 2C19 are responsible for stereoselective methadone metabolism in human liver microsomes and in vivo. Methods N-demethylation of racemic methadone and individual enantiomers by expressed CYPs 2B6, 2C19, and 3A4 was evaluated. Stereoselective microsomal methadone metabolism was quantified, compared with CYP 2B6 and 3A4 content, and probed using CYP isoform-selective inhibitors. A crossover clinical investigation (control, CYP2B6 and CYP3A4 induction by rifampin, CYP3A inhibition by troleandomycin and grapefruit juice) evaluated stereoselective methadone disposition. Results At clinical concentrations, methadone enantiomer N-demethylation by recombinant CYPs 2B6, 3A4, and 2C19 was S &gt; R, S = R, and S &lt; R. Greater stereoselective metabolism (S &gt; R) occurred in livers expressing high levels of CYP2B6 compared with CYP3A4. Clopidogrel, troleandomycin, and (+)-N-3-benzyl-nirvanol, selective inhibitors of CYPs 2B6, 3A4, and 2C19, respectively, inhibited microsomal methadone metabolism by 50-60%, 20-30%, and less than 10%. Only inhibition by clopidogrel was stereoselective. Clinically, rifampin diminished both R- and S-methadone plasma concentrations, but troleandomycin and grapefruit juice altered neither R- nor S-methadone concentrations. Plasma R/S-methadone ratios were increased by rifampin but unchanged by CYP3A inhibition. Conclusions These results suggest a significant role for CYP2B6, but not CYP3A, in stereoselective human methadone metabolism and disposition.

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Patel, Nirav D., Kanishka Chakrabory, Garrett Messmer, Koyamangalath Krishnan, and John B. Bossaer. "Severe sunitinib-induced myelosuppression in a patient with a CYP 3A4 polymorphism." Journal of Oncology Pharmacy Practice 24, no. 8 (2017): 623–26. http://dx.doi.org/10.1177/1078155217724863.

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Sunitinib, an oral vascular endothelial growth factor receptor, is a first-line option for metastatic renal cell carcinoma and widely used in clinical practice. Despite the proven benefit of sunitnib in metastatic renal cell carcinoma, patients may suffer from a variety of adverse events including hypertension, fatigue, hypothyroidism, hand–foot skin reactions, rash, depigmentation, and myelosuppression. Myelosuppression is usually mild, transient and resolves during the two weeks at the end of each cycle where no drug is taken. We present a case of severe and early grade 3 neutropenia and thrombocytopenia occurring two weeks into a six-week cycle. Because of the extreme nature of the toxicity, CYP 3A4 polymorphisms were explored. The patient was found to be heterozygous for CYP 3A4*22, at least partially explaining the early-onset and severity of myelosuppression. This pharmacogenetics information resulted in a rechallenge of dose-reduced sunitinib, which was well tolerated by the patient. The current state of pharmacogenomics concerning sunitinb is also presented, and the need for greater research in this area is highlighted.

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Larson, Brad, Timothy Moeller, Peter Banks, and James J. Cali. "Automated Triplexed Hepatocyte-Based Viability and CYP1A and -3A Induction Assays." Journal of Biomolecular Screening 16, no. 8 (2011): 895–902. http://dx.doi.org/10.1177/1087057111411482.

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Cytochrome P450 (CYP) enzymes are key players in drug metabolism. Therefore, it is essential to understand how these enzymes can be affected by xenobiotics with regards to induction and toxicity to avoid potential drug–drug interactions. Typically, information has been gathered by combining data from multiple experiments, which is time-consuming and labor intensive, and interassay variability may lead to misinterpretation. Monitoring CYP induction and cytotoxicity by xenobiotics using an automated, multiplexed format can decrease workload and increase data confidence. Here the authors demonstrate the ability to monitor CYP1A and CYP3A4 induction, combined with a cytotoxicity measurement, from a single microplate well using cryopreserved human hepatocytes. The assay procedure was automated in a 384-well format, including cell manipulations, compound titration and transfer, and reagent dispensing, using simple robotic instrumentation. EC50 and Emax values were derived for multiple known CYP1A and -3A4 inducers. Induction and toxicological responses in the triplex system were validated based on literature values from conventional single-parameter assays. Validation and pharmacology data confirm that multiplexed cell-based CYP assays can simplify workload, save time and effort, and generate biologically relevant data.

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Eaton, Ellen, Adam Wachter, Alan Tesson, and April A. Cooper. "Profound Neurotoxicity and Treatment Response following One Cycle of Bortezomib Therapy in an Elderly Male with Multiple Myeloma." Journal of Pharmacy Technology 28, no. 5 (2012): 193–96. http://dx.doi.org/10.1177/875512251202800503.

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Objective: To report a case of peripheral and autonomic neuropathy following one cycle of bortezomib in a patient with newly diagnosed multiple myeloma. Case Summary: A 75-year-old male who was highly functional prior to therapy rapidly became bed-bound from hypotension, syncope, and peripheral neuropathy after initiating bortezomib. Orthostatic hypotension and syncope persisted despite exclusion of infection and endocrine derangements and his receiving adequate intravenous hydration. Five weeks after this single cycle, the patient had a complete treatment response, including undetectable M-spike, improved anemia, and return to baseline renal function. An objective causality assessment revealed that an adverse drug event was probable. Discussion: Although neurotoxicity is an adverse effect of bortezomib, a MEDLINE search revealed little evidence on autonomic neuropathy, such as orthostatic hypotension and syncope. Also unique is the patient's complete treatment response following this single cycle. One explanation for the toxicities and dramatic treatment response is increased bortezomib exposure due to decreased drug metabolism. Both drug interactions and genetic polymorphisms can reduce bortezomib metabolism via effects on cytochrome P450 enzymes. Our patient was concomitantly taking 4 CYP inhibitors; amiodarone and omeprazole were longstanding, and ciprofloxacin and fluconazole were recently initiated prior to chemotherapy. Of these, fluconazole inhibits CYP2C9, 2C19, and 3A4; amiodarone inhibits CYP3A4, 1A1, 1A2, 2B6, and 2D6; ciprofloxacin inhibits CYP1A2 and 3A4; and omeprazole inhibits CYP1A2, 2C19, 2C9, 2D6, and 3A4. Similarly, genetic variables affect CYP enzymes. Genetic testing can predict response to bortezomib therapy, but pretherapy testing is not standard practice due to availability and cost, as in our patient's case. Conclusions: CYP-inhibiting drugs and many genetic polymorphisms can reduce bortezomib metabolism and increase serum concentrations of the drug, but guidelines on drug-drug interactions, monitoring, and genetic testing prior to bortezomib toxicity are needed.

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Adiraju, Santosh Kumar Sreevatsav, Kiran Shekar, Peter Tesar, et al. "Study Protocol for a Pilot, Open-Label, Prospective, and Observational Study to Evaluate the Pharmacokinetics of Drugs Administered to Patients during Extracorporeal Circulation; Potential of In Vivo Cytochrome P450 Phenotyping to Optimise Pharmacotherapy." Methods and Protocols 2, no. 2 (2019): 38. http://dx.doi.org/10.3390/mps2020038.

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Pharmacokinetic alterations of medications administered during surgeries involving cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) have been reported. The impact of CPB on the cytochrome P450 (CYP) enzymes’ activity is the key factor. The metabolic rates of caffeine, dextromethorphan, midazolam, omeprazole, and Losartan to the CYP-specific metabolites are validated measures of in vivo CYP 1A2, 2D6, 3A4, 2C19, and 2C9 activities, respectively. The study aim is to assess the activities of major CYPs in patients on extracorporeal circulation (EC). This is a pilot, prospective, open-label, observational study in patients undergoing surgery using EC and patients undergoing laparoscopic cholecystectomy as a control group. CYP activities will be measured on the day, and 1–2 days pre-surgery/3–4 days post-surgery (cardiac surgery and Laparoscopic cholecystectomy) and 1–2 days after starting ECMO, 1–2 weeks after starting ECMO, and 1–2 days after discontinuation from ECMO. Aforementioned CYP substrates will be administered to the patient and blood samples will be collected at 0, 1, 2, 4, and 6 h post-dose. Major CYP enzymes’ activities will be compared in each participant on the day, and before/after surgery. The CYP activities will be compared in three study groups to investigate the impact of CYPs on EC.

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Kariv, Ilona, Mark P. Fereshteh, and Kevin R. Oldenburg. "Development of a Miniaturized 384-Well High Throughput Screen for the Detection of Substrates of Cytochrome P450 2D6 and 3A4 Metabolism." Journal of Biomolecular Screening 6, no. 2 (2001): 91–99. http://dx.doi.org/10.1177/108705710100600205.

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The identification of a large number of biologically active chemical entities during high throughput screening (HTS) necessitates the incorporation of new strategies to identify compounds with druglike properties early during the lead prioritization and development process. One of the major steps in lead prioritization is the assessment of drug metabolism mediated by the cytochrome P450 (CYP) enzymes to evaluate the potential drug-drug interactions. CYP2D6 and CYP3A4 comprise the main human CYP enzymes involved in drug metabolism. The recent availability of specific CYP cDNA expression systems and the development of specific fluorescent probes have accelerated the ability to develop robust in vitro assays in HTS format. The aim of this study was to optimize conditions for the CYP2D6 and CYP3A4 HTS assays and subsequently adapt those assays to a miniaturized 384-well format. Assay conversion to a miniaturized format presents certain difficulties, such as robustness of the signal and of compound delivery. Thus the assay optimization involved the comparison of different substrates to identify those most suitable for use in a miniaturized format. Because of current technical limitations in liquid dispensing of nanoliter volumes, assay sensitivity to organic solvents also provides a main concern during assay miniaturization. Therefore, compound activity from redissolved dry films and from DMSO stocks directly delivered into assay buffer was compared. The data indicate that compound activity was comparable in both formats. The data support the conclusion that CYP2D6 and CYP3A4 in vitro metabolism assays can be successfully performed in 384-well plate format and the substrate potencies, as evaluated by the IC50 values, determined.

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Wu, Qiangen, Baitang Ning, Jiekun Xuan, Zhen Ren, Lei Guo, and Matthew S. Bryant. "The role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity." Toxicology Letters 253 (June 2016): 55–62. http://dx.doi.org/10.1016/j.toxlet.2016.04.016.

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Varughese, George I., and John Hb Scarpello. "Non-Traumatic Rhabdomyolysis: The Emerging Role of CYP 3A4 in Diabetes Mellitus." Journal of the Royal Society of Medicine 99, no. 8 (2006): 385–86. http://dx.doi.org/10.1177/014107680609900808.

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Varughese, G. I. "Non-traumatic rhabdomyolysis: the emerging role of CYP 3A4 in diabetes mellitus." Journal of the Royal Society of Medicine 99, no. 8 (2006): 385–86. http://dx.doi.org/10.1258/jrsm.99.8.385-b.

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Shord, S. "Oral clotrimazole (CLZ) decreases presystemic metabolism of cytochrome P450 (CYP) 3A4 substrates." Clinical Pharmacology & Therapeutics 75, no. 2 (2004): P31. http://dx.doi.org/10.1016/j.clpt.2003.11.117.

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Campelo, Diana, Francisco Esteves, Bernardo Brito Palma, et al. "Probing the Role of the Hinge Segment of Cytochrome P450 Oxidoreductase in the Interaction with Cytochrome P450." International Journal of Molecular Sciences 19, no. 12 (2018): 3914. http://dx.doi.org/10.3390/ijms19123914.

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NADPH-cytochrome P450 reductase (CPR) is the unique redox partner of microsomal cytochrome P450s (CYPs). CPR exists in a conformational equilibrium between open and closed conformations throughout its electron transfer (ET) function. Previously, we have shown that electrostatic and flexibility properties of the hinge segment of CPR are critical for ET. Three mutants of human CPR were studied (S243P, I245P and R246A) and combined with representative human drug-metabolizing CYPs (isoforms 1A2, 2A6 and 3A4). To probe the effect of these hinge mutations different experimental approaches were employed: CYP bioactivation capacity of pre-carcinogens, enzyme kinetic analysis, and effect of the ionic strength and cytochrome b5 (CYB5) on CYP activity. The hinge mutations influenced the bioactivation of pre-carcinogens, which seemed CYP isoform and substrate dependent. The deviations of Michaelis-Menten kinetic parameters uncovered tend to confirm this discrepancy, which was confirmed by CYP and hinge mutant specific salt/activity profiles. CPR/CYB5 competition experiments indicated a less important role of affinity in CPR/CYP interaction. Overall, our data suggest that the highly flexible hinge of CPR is responsible for the existence of a conformational aggregate of different open CPR conformers enabling ET-interaction with structural varied redox partners.

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Vennapanja, Prashanth, and Ajmera Ramarao. "Effect of lopinavir and efavirenz on pharmacokinetics and pharmacodynamics of glibenclamide in diabetic rats." Pharmaceutical and Biological Evaluations 4, no. 6 (2017): 245. http://dx.doi.org/10.26510/2394-0859.pbe.2017.38.

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Objective: The aim of the study is whether the impact of Efavirenz and Lopinavir will increase the plasma level of Glibenclamide or not. Efavirenz and Lopinavir is an antiretroviral drug to treat HIV AIDS and inhibits cytochrome P450-3A4. Multiple CYP isoforms are involved in the metabolism of Glibenclamide like CYP2C8 and CYP3A4. Hence there is more possibility of Efavirenz and Lopinavir to inhibit the metabolism of Glibenclamide by inhibiting CYP 3A4.Methods: Efavirenz and Lopinavir (10 mg/kg,p.o.) alone and along with Glibenclamide (10 mg/kg, p.o.) was given to normal and diabetic rats. PK/PD parameters were studied. In the rats co-treated with Efavirenz and Lopinavir and Glibenclamide.Results: The pharmacokinetic parameters like clearance of Glibenclamide was reduced, peak plasma concentration, area under the plasma concentration time curve and elimination half-life were significantly increased when compared to pioglitazone treated rats.Conclusions: This study revealed that lopinavir and efavirenz affected the disposition of Glibenclamide in rats probably by the inhibition of CYP3A4, leading to increasing Glibenclamide concentrations that could increase the efficacy of Glibenclamide or it may causes severe hypoglycemia. Therefore, its warrants to use relatively less dose of Glibenclamide than the normal dose.

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Sizova, Zh M., E. V. Shikh, and A. A. Makhova. "Significance of L-carnitine in internal medicine." Terapevticheskii arkhiv 91, no. 1 (2019): 114–20. http://dx.doi.org/10.26442/00403660.2019.01.000040.

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The review presents the results of a number of experimental and clinical studies proving the prospects of using L-carnitine in the clinic of internal diseases. Due to the antioxidant and antihypoxant properties, the additional use of L-carnitine in addition to the main etiopathogenetic therapy is prescribed by cardiologists, nephrologists, neurologists, gerontologists. Experimental studies we conducted earlier showed no effect of L-carnitine on the activity of the P450 CYP 3A4 system, which reduces the likelihood of drug-drug interaction at the level of metabolism of drugs metabolized by P450 3A4. When using L-carnitine as part of complex pharmacotherapy, the drug has an increased safety profile in comorbid patients taking L-carnitine.

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Cott, Jerry M. "Herb-Drug Interactions: Focus on Pharmacokinetics." CNS Spectrums 6, no. 10 (2001): 827–32. http://dx.doi.org/10.1017/s1092852900001644.

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ABSTRACTRecent literature regarding drug-drug, herb-drug, and food-drug interactions must not be ignored; nor can they always be taken at face value. Studies have shown that St. John's wort (SJW)(Hypericum perforatum) can reduce plasma levels of indinavir, cyclosporin, digoxin, and possibly other drugs as well. Current knowledge regarding the metabolism of these medications suggests that the cytochrome P450 (CYP) drug metabolizing enzyme systems cannot account for all these effects. It has been reported that the P-glycoprotein (Pgp) transmembrane pump is also induced by SJW. Medications that are substrates of both CYP 3A4 a Pgp are of particular concern and may pose special interaction risks when combined with certain foods or botanical products such as SJW.

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Standop, Jens, Matthias Schneider, Alexis Ulrich, Markus W. Büchler, and Parviz M. Pour. "Differences in Immunohistochemical Expression of Xenobiotic-Metabolizing Enzymes Between Normal Pancreas, Chronic Pancreatitis and Pancreatic Cancer." Toxicologic Pathology 31, no. 5 (2003): 506–13. http://dx.doi.org/10.1080/01926230390226041.

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Metabolic activation of many toxins, carcinogens, drugs, and anti-cancer agents is governed by the cytochrome P450 (CYP) drug-metabolizing enzyme system. To help elucidate the role of this enzyme system in the pathogenesis of chronic inflammatory and malignant pancreatic diseases, we compared the immunohistochemical expression pattern of 8 CYP-enzymes in 24 normal, 20 chronic pancreatitis, and 21 pancreatic cancer specimens using antibodies to CYP 1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, and 3A4, and the NADPH cytochrome P450 oxido-reductase (NA-OR). Compared to the normal pancreas, a higher frequency of immunopositivity for CYP 1A2, 2B6, 2C8/9/19, 2D6, and NA-OR was found in chronic pancreatitis, and of all CYPs but 1A2 in pancreatic cancer. On the other hand, CYP 1A1 and 2E1 antibody staining was less frequently observed in chronic pancreatitis. In all specimens with pancreatic polypeptide (PP)-rich regions (pancreas head), more islet cells than ductal and acinar cells were immunopositive. Moreover, the immunoreactivity of islet cells from PP-rich specimens with anti-CYP antibodies was consistently more frequent and intense than in islet cells from PP-poor areas (body and tail). Immunoreactivity for xenobiotic-metabolizing enzymes was frequently observed in the normal pancreas, chronic pancreatitis, and pancreatic cancer, and displayed differences of its frequency and intensity between the 3 groups. Considering immunohistochemical evidence of enzyme expression and pancreatic blood supply together, islet cells appear to be an important and possible early site of CYP-enzyme induction in pancreatic diseases.

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Mohos, Violetta, Eszter Fliszár-Nyúl, Orsolya Ungvári, et al. "Inhibitory Effects of Quercetin and Its Main Methyl, Sulfate, and Glucuronic Acid Conjugates on Cytochrome P450 Enzymes, and on OATP, BCRP and MRP2 Transporters." Nutrients 12, no. 8 (2020): 2306. http://dx.doi.org/10.3390/nu12082306.

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Quercetin is a flavonoid, its glycosides and aglycone are found in significant amounts in several plants and dietary supplements. Because of the high presystemic biotransformation of quercetin, mainly its conjugates appear in circulation. As has been reported in previous studies, quercetin can interact with several proteins of pharmacokinetic importance. However, the interactions of its metabolites with biotransformation enzymes and drug transporters have barely been examined. In this study, the inhibitory effects of quercetin and its most relevant methyl, sulfate, and glucuronide metabolites were tested on cytochrome P450 (CYP) (2C19, 3A4, and 2D6) enzymes as well as on organic anion-transporting polypeptides (OATPs) (OATP1A2, OATP1B1, OATP1B3, and OATP2B1) and ATP (adenosine triphosphate) Binding Cassette (ABC) (BCRP and MRP2) transporters. Quercetin and its metabolites (quercetin-3′-sulfate, quercetin-3-glucuronide, isorhamnetin, and isorhamnetin-3-glucuronide) showed weak inhibitory effects on CYP2C19 and 3A4, while they did not affect CYP2D6 activity. Some of the flavonoids caused weak inhibition of OATP1A2 and MRP2. However, most of the compounds tested proved to be strong inhibitors of OATP1B1, OATP1B3, OATP2B1, and BCRP. Our data demonstrate that not only quercetin but some of its conjugates, can also interact with CYP enzymes and drug transporters. Therefore, high intake of quercetin may interfere with the pharmacokinetics of drugs.

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Teschke, Rolf, Noudeng Vongdala, Nguyen Van Quan, Tran Ngoc Quy, and Tran Dang Xuan. "Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update." International Journal of Molecular Sciences 22, no. 19 (2021): 10419. http://dx.doi.org/10.3390/ijms221910419.

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Saturated and unsaturated pyrrolizidine alkaloids (PAs) are present in more than 6000 plant species growing in countries all over the world. They have a typical heterocyclic structure in common, but differ in their potential toxicity, depending on the presence or absence of a double bond between C1 and C2. Fortunately, most plants contain saturated PAs without this double bond and are therefore not toxic for consumption by humans or animals. In a minority of plants, however, PAs with this double bond between C1 and C2 exhibit strong hepatotoxic, genotoxic, cytotoxic, neurotoxic, and tumorigenic potentials. If consumed in error and in large emouns, plants with 1,2-unsaturated PAs induce metabolic breaking-off of the double bonds of the unsaturated PAs, generating PA radicals that may trigger severe liver injury through a process involving microsomal P450 (CYP), with preference of its isoforms CYP 2A6, CYP 3A4, and CYP 3A5. This toxifying CYP-dependent conversion occurs primarily in the endoplasmic reticulum of the hepatocytes equivalent to the microsomal fraction. Toxified PAs injure the protein membranes of hepatocytes, and after passing their plasma membranes, more so the liver sinusoidal endothelial cells (LSECs), leading to life-threatening hepatic sinusoidal obstruction syndrome (HSOS). This injury is easily diagnosed by blood pyrrolizidine protein adducts, which are perfect diagnostic biomarkers, supporting causality evaluation using the updated RUCAM (Roussel Uclaf Causality Assessment Method). HSOS is clinically characterized by weight gain due to fluid accumulation (ascites, pleural effusion, and edema), and may lead to acute liver failure, liver transplantation, or death. In conclusion, plant-derived PAs with a double bond between C1 and C2 are potentially hepatotoxic after metabolic removal of the double bond, and may cause PA-HSOS with a potential lethal outcome, even if PA consumption is stopped.

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Liu, Xing-Jie, Hua Lu, Ju-Xiang Sun, et al. "Metabolic behavior prediction of pazopanib by cytochrome P450 (CYP) 3A4 by molecular docking." European Journal of Drug Metabolism and Pharmacokinetics 41, no. 4 (2015): 465–68. http://dx.doi.org/10.1007/s13318-015-0252-y.

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González-Vázquez, María Dolores, Marta Sofia Rafael-Marques, Susana Marques-de Sousa, Maria Alexandra Duarte, and Ângela Daniela Coelho. "No existen fármacos inocentes: daño hepatocelular inducido por desloratadina." Revista Española de Casos Clínicos en Medicina Interna 4, no. 3 (2019): 111–14. http://dx.doi.org/10.32818/reccmi.a4n3a4.

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Los síntomas, signos y alteraciones de la función hepática inducidos por fármacos pueden mimetizar cualquier tipo de enfermedad hepática. Se presenta un caso de lesión hepatocelular por desloratadina. La desloratadina es un fármaco metabolizado por hígado vía citocromo P450 (CYP 3A4 y 2D6), con escasa referencia en la literatura como causa de daño hepático. Se enfatiza la importancia de la vigilancia de la función hepática en pacientes tratados con fármacos con potencial hepatotóxico.

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Benkaidali, Lydia, François André, Gautier Moroy, Bahoueddine Tangour, François Maurel, and Michel Petitjean. "Four Major Channels Detected in the Cytochrome P450 3A4: A Step toward Understanding Its Multispecificity." International Journal of Molecular Sciences 20, no. 4 (2019): 987. http://dx.doi.org/10.3390/ijms20040987.

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We computed the network of channels of the 3A4 isoform of the cytochrome P450 (CYP) on the basis of 16 crystal structures extracted from the Protein Data Bank (PDB). The calculations were performed with version 2 of the CCCPP software that we developed for this research project. We identified the minimal cost paths (MCPs) output by CCCPP as probable ways to access to the buried active site. The algorithm of calculation of the MCPs is presented in this paper, with its original method of visualization of the channels. We found that these MCPs constitute four major channels in CYP3A4. Among the many channels proposed by Cojocaru et al. in 2007, we found that only four of them open in 3A4. We provide a refined description of these channels together with associated quantitative data.

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Beck, Tyler C., Kyle R. Beck, Jordan Morningstar, Menny M. Benjamin, and Russell A. Norris. "Descriptors of Cytochrome Inhibitors and Useful Machine Learning Based Methods for the Design of Safer Drugs." Pharmaceuticals 14, no. 5 (2021): 472. http://dx.doi.org/10.3390/ph14050472.

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Roughly 2.8% of annual hospitalizations are a result of adverse drug interactions in the United States, representing more than 245,000 hospitalizations. Drug–drug interactions commonly arise from major cytochrome P450 (CYP) inhibition. Various approaches are routinely employed in order to reduce the incidence of adverse interactions, such as altering drug dosing schemes and/or minimizing the number of drugs prescribed; however, often, a reduction in the number of medications cannot be achieved without impacting therapeutic outcomes. Nearly 80% of drugs fail in development due to pharmacokinetic issues, outlining the importance of examining cytochrome interactions during preclinical drug design. In this review, we examined the physiochemical and structural properties of small molecule inhibitors of CYPs 3A4, 2D6, 2C19, 2C9, and 1A2. Although CYP inhibitors tend to have distinct physiochemical properties and structural features, these descriptors alone are insufficient to predict major cytochrome inhibition probability and affinity. Machine learning based in silico approaches may be employed as a more robust and accurate way of predicting CYP inhibition. These various approaches are highlighted in the review.

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Teschke, Rolf, and Gaby Danan. "Idiosyncratic Drug Induced Liver Injury, Cytochrome P450, Metabolic Risk Factors and Lipophilicity: Highlights and Controversies." International Journal of Molecular Sciences 22, no. 7 (2021): 3441. http://dx.doi.org/10.3390/ijms22073441.

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Progress in understanding the mechanisms of the idiosyncratic drug induced liver injury (iDILI) was highlighted in a scientometric investigation on the knowledge mapping of iDILI throughout the world, but uncertainty remained on metabolic risk factors of iDILI, the focus of the present review article. For the first time, a quantitative analysis of 3312 cases of iDILI assessed for causality with RUCAM (Roussel Uclaf Causality Assessment Method) showed that most drugs (61.1%) were metabolized by cytochrome P450 (CYP) isoforms: 49.6% by CYP 3A4/5, 24.6% by CYP 2C9, 13.2% by CYP 2E1, 7.3% by CYP 2C19, 3.5% by CYP 1A2 and 1.8% by CYP 2D6. Other studies showed high OR (odds ratio) for drugs metabolized by unspecified CYPs but the iDILI cases were not assessed for causality with RUCAM, a major shortcoming. In addition to critical comments on methodological flaws, several risk factors of iDILI were identified such as high but yet recommended daily drug doses, actual daily drug doses taken by the patients, hepatic drug metabolism and drug lipophilicity. These risk factors are subject to controversies by many experts seen critically also by others who outlined that none of these medication characteristics is able to predict iDILI with high confidence, leading to the statement of an outstanding caveat. It was also argued that all previous studies lacked comprehensive data because the number of examined drugs was relatively small as compared to the number of approved new molecular entities or currently used oral prescription drugs. In conclusion, trends are evident that some metabolic parameters are likely risk factors of iDILI but strong evidence can only be achieved when methodological issues will be successfully met.

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Saghir, Shakil A., Burhan I. Ghanayem, and Irvin R. Schultz. "Kinetics of Trihalogenated Acetic Acid Metabolism and Isoform Specificity in Liver Microsomes." International Journal of Toxicology 30, no. 5 (2011): 551–61. http://dx.doi.org/10.1177/1091581811414213.

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This study determined the metabolism of 3 drinking water disinfection by-products (halogenated acetic acids [HAAs]), bromodichloroacetic acid (BDCAA), chlorodibromoacetic acid (CDBAA), and tribromoacetic acid (TBAA), using rat, mouse, human liver microsomes, and recombinant P450. Metabolism proceeded by reductive debromination forming a di-HAA; the highest under nitrogen >>2% oxygen > atmospheric headspaces. Vmax for the loss of tri-HAA was 4 to 5 times higher under nitrogen than atmospheric headspace. Intrinsic metabolic clearance was TBAA>CDBAA>>BDCAA. At the high substrate concentrations, tri-HAA consumption rate was 2 to 3 times higher than the formation of di-HAA. Liberation of Br− from TBAA corresponded to the expected amount produced after DBAA formation, indicating retention of Br− by additional metabolite/metabolites. Subsequent experiments with CDBAA detected negligible formation of chlorodibromomethane (CDBM) and failed to account for the missing tri-HAA. Carbon monoxide and especially diphenyleneiodonium ([DPI] P450 reductase inhibitor) blocked CDBAA metabolism. Other chemical inhibitors were only partially able to block CDBAA metabolism. Most effective were inhibitors of CYP 2E1 and CYP 3A4. Immunoinhibition studies using human liver microsomes and anti-human CYP 2E1 antibodies were successful in reducing CDBAA metabolism. However, CDBAA metabolism in wild-type (WT) and CYP 2E1 knockout (KO) mouse liver microsomes was similar, suggesting significant interspecies differences in CYP isoform in tri-HAA metabolism. Additional assessment of CYP isoform involvement was complicated by the finding that recombinantly expressed rat and human P450 reductase was able to metabolize CDBAA, which may be a contributing factor in interspecies differences in tri-HAA metabolism.

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