Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs

Zhou, Shufeng, Chan, Sui Yung, Goh, Boon Cher, Chan, Eli, Duan, Wei, Huang, Min and McLeod, Howard L 2005, Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs, Clinical pharmacokinetics, vol. 44, no. 3, pp. 279-304.

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Title Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs
Author(s) Zhou, Shufeng
Chan, Sui Yung
Goh, Boon Cher
Chan, Eli
Duan, WeiORCID iD for Duan, Wei
Huang, Min
McLeod, Howard L
Journal name Clinical pharmacokinetics
Volume number 44
Issue number 3
Start page 279
End page 304
Publisher Adis International Ltd.
Place of publication Auckland, New Zealand
Publication date 2005
ISSN 0312-5963
Keyword(s) Pharmaceutical Preparations
Cytochrome P-450 Enzyme System -- antagonists & inhibitors
Enzyme Inhibitors -- pharmacokinetics
Enzyme Inhibitors -- pharmacology
Summary Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches using in vitro, in silico and in vivo models can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (K(I)) and the maximal rate of inactivation at saturation (k(inact)).Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs.Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of its K(I), k(inact) and partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confounding in vitro-in vivo extrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.
Language eng
Field of Research 111502 Clinical Pharmacology and Therapeutics
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2005, Adis Data Information B.V.
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Document type: Journal Article
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