Comparison of rat and human cytochrome P450 (CYP) sources ofN-alkylprotoporphyrin IX. Formation after interaction with porphyrinogenic xenobiotics: studies with cDNA-expressed single CYP enzymes

ABSTRACT Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, <6 μM); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (<25% inhibition at 100 μM voriconazole). Further detailed experiments with HLMs showed that voriconazole is a potent competitive inhibitor of CYP2B6 (Ki < 0.5), CYP2C9 (Ki = 2.79 μM), and CYP2C19 (Ki = 5.1 μM). The inhibition of CYP3A by voriconazole was explained by noncompetitive (Ki = 2.97 μM) and competitive (Ki = 0.66 μM) modes of inhibition. Prediction of the in vivo interaction of voriconazole from these in vitro data suggests that voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.

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No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P‐glycoprotein (P‐gp) drug transporter

Pharmacology Research & Perspectives ◽

10.1002/prp2.540 ◽

2019 ◽

Vol 7 (6) ◽

Cited By ~ 1

Author(s):

Jordi Aubets ◽

Josep‐Maria Jansat ◽

Miquel Salva ◽

Vicky M. Birks ◽

Richard J. Cole ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Transporter ◽

Main Metabolite ◽

Glycoprotein P ◽

Cyp Enzymes ◽

P Glycoprotein ◽

Human Cytochrome

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Metabolism and mechanism of human cytochrome P450 enzyme 1A2

Current Drug Metabolism ◽

10.2174/1389200221999210101233135 ◽

2021 ◽

Vol 21 ◽

Author(s):

Jingchao Guo ◽

Xiaohui Zhu ◽

Sara Badawy ◽

Awais Ihsan ◽

Zhenli Liu ◽

...

Keyword(s):

Cytochrome P450 ◽

Aromatic Hydrocarbon ◽

Personalised Medicine ◽

Cytochrome P450 Enzyme ◽

Cyp Enzymes ◽

Human Cytochrome ◽

P450 Enzyme ◽

Metabolic Mechanism ◽

Clinical Drugs ◽

Human Cytochrome P450 Enzyme

Abstract: Human cytochrome P450 enzyme 1A2 (CYP1A2) is one of the most important cytochrome P450 (CYP) enzymes in the liver, accounting for 13% to 15% of hepatic CYP enzymes. CYP1A2 metabolises many clinical drugs, such as phenacetin, caffeine, clozapine, tacrine, propranolol, and mexiletine. CYP1A2 also metabolises certain precarcinogens such as aflatoxins, mycotoxins, nitrosamines, and endogenous substances such as steroids. The regulation of CYP1A2 is influenced by many factors. The transcription of CYP1A2 involves not only the aromatic hydrocarbon receptor pathway, but also many additional transcription factors, and CYP1A2 expression may be affected by transcription coactivators and compression factors. Degradation of CYP1A2 mRNA and protein, alternative splicing, RNA stability, regulatory microRNAs, and DNA methylation are also known to affect the regulation of CYP1A2. Many factors can lead to changes in the activity of CYP1A2. Smoking, polycyclic aromatic hydrocarbon ingestion, and certain drugs (e.g., omeprazole) increase its activity, while many clinical drugs such as theophylline, fluvoxamine, quinolone antibiotics, verapamil, cimetidine, and oral contraceptives can inhibit CYP1A2 activity. Here, we review the drugs metabolised by CYP1A2, the metabolic mechanism of CYP1A2, and various factors that influence CYP1A2 metabolism. The metabolic mechanism of CYP1A2 is of great significance in the development of personalised medicine and CYP1A2 target-based drugs.

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Update Information on Drug Metabolism Systems— 2009, Part II. Summary of Information on the Effects of Diseases and Environmental Factors on Human Cytochrome P450 (CYP) Enzymes and Transporters

Current Drug Metabolism ◽

10.2174/138920010791110917 ◽

2010 ◽

Vol 11 (1) ◽

pp. 4-84 ◽

Cited By ~ 69

Author(s):

Slobodan Rendic ◽

F. Peter Guengerich

Keyword(s):

Cytochrome P450 ◽

Environmental Factors ◽

Drug Metabolism ◽

Cyp Enzymes ◽

Human Cytochrome

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The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions

Pharmacological Reports ◽

10.1007/s43440-020-00102-5 ◽

2020 ◽

Vol 72 (6) ◽

pp. 1685-1694 ◽

Cited By ~ 1

Author(s):

Przemysław J. Danek ◽

Jacek Wójcikowski ◽

Władysława A. Daniel

Keyword(s):

Cytochrome P450 ◽

Combined Therapy ◽

Liver Microsomes ◽

Atypical Neuroleptics ◽

Cytochrome P450 Enzymes ◽

Cyp Enzymes ◽

Human Cytochrome ◽

Competitive Mechanism ◽

Mixed Mechanism

Abstract Background The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes). Methods The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3-N-demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, perazine N-demethylation/CYP2C19, bufuralol 1′-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC. Results Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (Ki = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism (Ki = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 (Ki = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 (Ki = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 (Ki = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism (Ki = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity (Ki = 37.5 and 85 µM in microsomes and supersomes). Conclusion The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.

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