Pharmacogenomics of the cytochrome P450 2C family: impacts of amino acid variations on drug metabolism

Isvoran, Adriana; Louet, Maxime; Vlădoiu, Diana Larisa; Crăciun, Dana; Loriot, Marie‐Anne; Villoutreix, Bruno O.; Miteva, Maria A.

doi:10.1016/j.drudis.2016.09.015

Cited by 62 publications

(46 citation statements)

References 94 publications

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“…CYP450 is a supergene family of drug-metabolizing enzymes responsible for the metabolism of approximately 75% of clinically administered drugs [10, 11]. The greatest contributor to the biotransformation of drugs in human is CYP3A4/5, followed by CYP2D6, CYP2C6, CYP1A2, and others [12].…”

Section: Introductionmentioning

confidence: 99%

Influences of Anlotinib on Cytochrome P450 Enzymes in Rats Using a Cocktail Method

Wei

Wang

Chen

et al. 2017

BioMed Research International

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The present study aimed to investigate the effect of anlotinib (AL3818) on pharmacokinetics of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C6, CYP2D1, CYP2D2, and CYP3A1/2) by using five cocktail probe drugs in vivo. After pretreatment for 7 days with anlotinib (treatment group) or saline (control group) by oral administration, probe drugs phenacetin, tolbutamide, omeprazole, metoprolol, and midazolam were administered to rats by oral administration. Blood samples were obtained at a series of time-points and the concentrations of five probe drugs in plasma were determined by a UHPLC-MS/MS method. The results showed that treatment with anlotinib had no significant effect on rat CYP1A2, CYP2D2, and CYP2C6. However, anlotinib had a significant inductive effect on CYP2D1 and CYP3A1/2. Therefore, caution is needed during the concomitant use of anlotinib with other drugs metabolized by CYP2D1 and CYP3A1/2 because of potential drug-anlotinib interactions.

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Section: Introductionmentioning

confidence: 99%

Influences of Anlotinib on Cytochrome P450 Enzymes in Rats Using a Cocktail Method

Wei

Wang

Chen

et al. 2017

BioMed Research International

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“…The early homology models of CYPs have enabled the first ADMET prediction based on 3D structures of proteins that can complement the data‐derived models in order to move toward a deeper mechanistic prediction. Numerous X‐ray structures of human CYP proteins are now available in Protein Data Bank (PDB) that enable prediction of ligand binding in CYP for metabolism or inhibition mechanism prediction, , ). Recently, we developed an original in silico approach to predict inhibition of CYP2D6 (a protein that metabolizes about 30 % of the drugs) by combining the knowledge of the protein structure and its dynamic behavior in response to the binding of various ligands and machine learning modeling (Fig.2).…”

Section: D‐admet: Overall Concepts and Applications In Mtimentioning

confidence: 99%

Computational Biology and Chemistry in MTi: Emphasis on the Prediction of Some ADMET Properties

Villoutreix

2017

Molecular Informatics

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Our research and teaching group called MTi (Molécules Thérapeutiques in silico) has developed numerous applications available online, thanks to the RPBS platform (Ressource Parisienne en Bioinformatique Structurale), in the field of chemoinformatics, structural bioinformatics and drug design. Since its opening in 2009, over 200 articles/reviews have been reported and involve virtual screening studies, prediction of druggability, analysis of protein-protein interaction inhibitors, development of databases, data mining and knowledge discovery, as well as combined in silico-in vitro work to search for new hits and chemical probes acting on original targets in several therapeutic areas. An international training program has also been developed pertaining to the field of in silico drug design. In this review, we present some tools developed in our laboratory with a special emphasis on the prediction of some ADMET properties, compound collection preparation and 3D-ADMET computations.

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“…Cytochrome P450s (CYPs) in the liver play a central role in the metabolic removal of most clinical drugs, and modification of the metabolic functions of hepatic CYP enzymes has been recognized as a major cause of drug interactions encountered in clinical practice (Zanger & Schwab, ). CYPs are classified into several subtypes, and CYP2C is regarded as one of the most important subfamilies since the metabolic removal of approximately 20% of clinically used drugs is mediated by the CYP2C subfamily (Isvoran et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…This finding provides experimental evidence that doxorubicin exposure is likely to down‐regulate hepatic CYP2C11 by interfering with pre‐translational regulation, but it remains unclear whether the decreased CYP2C11 expression leads to the pharmacokinetic change of drugs subject to metabolic elimination by CYP2C11 because the expression level of CYP proteins is not necessarily related to their metabolic activities (Fukuno, Nagai, Fujiike, Sasaki, & Konishi, ; Nagai et al, ). CYP2C9 is a major constituent of the human CYP2C subfamily and it is involved in the oxidative biotransformation of many drugs with narrow therapeutic ranges (Isvoran et al, ). On the other hand, rat CYP2C11 and CYP2C6 have both been recognized as counterparts of human CYP2C9 based on substrate preference, specificity and DNA sequence homology (Bogaards et al, ; Daniel, Haduch, Syrek, & Boksa, ; Lewis, ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic interference of doxorubicin with tolbutamide due to reduced metabolic clearance with increased serum unbound fraction in rats

Fukuno

Nagai

Yamamoto

et al. 2019

Biopharm & Drug Disp

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The study examined the effect of doxorubicin (DOX) on the hepatic expression of CYP2C and its activity for metabolizing tolbutamide (TB), a specific CYP2C substrate, in rats and whether the pharmacokinetics of tolbutamide were altered by doxorubicin exposure. The expression level of hepatic CYP2C11 was depressed 1 day after doxorubicin administration (day 1), and this effect on CYP2C11 was augmented on day 4. However, the expression level of hepatic CYP2C6 remained unchanged. The activity of tolbutamide 4‐hydroxylation in hepatic microsomes was decreased with time following doxorubicin administration. Regarding the enzyme kinetic parameters for tolbutamide 4‐hydroxylation on day 4, the maximum velocity (Vmax) was significantly lower in the DOX group than that in the control group, while the Michaelis constant (Km) was unaffected. On pharmacokinetic examination, the total clearance (CLtot) of tolbutamide on day 4 was increased, despite the decreased metabolic capacity. On the other hand, the serum unbound fraction (fu) of tolbutamide was elevated with a reduced serum albumin concentration in the DOX group. Contrary to CLtot, CLtot/fu, a parameter approximated to the hepatic intrinsic clearance of unbound tolbutamide, was estimated to be significantly reduced in the DOX group. These findings indicate that the metabolic capacity of CYP2C11 in the liver is depressed time‐dependently by down‐regulation after doxorubicin exposure in rats, and that the decreased enzyme activity of TB 4‐hydroxylation in hepatic microsomes reflects the pharmacokinetic change of unbound tolbutamide, not total tolbutamide, in serum.

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Pharmacogenomics of the cytochrome P450 2C family: impacts of amino acid variations on drug metabolism

Cited by 62 publications

References 94 publications

Influences of Anlotinib on Cytochrome P450 Enzymes in Rats Using a Cocktail Method

Influences of Anlotinib on Cytochrome P450 Enzymes in Rats Using a Cocktail Method

Computational Biology and Chemistry in MTi: Emphasis on the Prediction of Some ADMET Properties

Pharmacokinetic interference of doxorubicin with tolbutamide due to reduced metabolic clearance with increased serum unbound fraction in rats

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