Characterization of Cytochrome P450 Mechanism‐Based Inhibition

Rock, Dan A.; Wienkers, Larry C.

doi:10.1002/9780470439265.ch18

Cited by 3 publications

(2 citation statements)

References 155 publications

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“…The number of drugs that have been characterized as mechanism-based inactivators (MBIs) has been increasing because of our greater understanding of its clinical importance. There are several criteria used in the characterization of MBIs: time-dependence of inactivation, saturable kinetics of inactivation with respect to inhibitor concentration, inactivation in a catalytically competent system, substrate protection of enzyme from inactivation, lack of suppression of inactivation by exogenous nucleophiles, irreversibility of inactivation, and 1:1 binding stoichiometry of inactivator to inactivated enzyme (Rock et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib

Teng¹,

Oh²,

New³

et al. 2010

Mol Pharmacol

105

138

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Fatalities stemming from hepatotoxicity associated with the clinical use of lapatinib (Tykerb), an oral dual tyrosine kinase inhibitor (ErbB-1 and ErbB-2) used in the treatment of metastatic breast cancer, have been reported. We investigated the inhibition of CYP3A4 by lapatinib as a possible cause of its idiosyncratic toxicity. Inhibition of CYP3A4 was time-, concentration-, and NADPH-dependent, with k inact ϭ 0.0202 min Ϫ1 and K i ϭ 1.709 M. The partition ratio was approximately 50.9. Addition of GSH did not affect the rate of inactivation. Testosterone protected CYP3A4 from inactivation by lapatinib. The characteristic Soret peak associated with a metabolite-intermediate complex was not observed for lapatinib during spectral difference scanning. However, reduced carbon monoxide (CO)-difference spectroscopy did reveal a 43% loss of the spectrally detectable CYP3A4-CO complex in the presence of lapatinib. Incubation of either lapatinib or its dealkylated metabolite with human liver microsomes in the presence of GSH resulted in the formation of a reactive metabolite (RM)-GSH adduct derived from the O-dealkylated metabolite of lapatinib. In addition, coincubation of lapatinib with ketoconazole inhibited the formation of the RM-GSH adduct. In conclusion, we demonstrated for the first time that lapatinib is a mechanism-based inactivator of CYP3A4, most likely via the formation and further oxidation of its O-dealkylated metabolite to a quinoneimine that covalently modifies the CYP3A4 apoprotein and/or heme moiety.

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Section: Introductionmentioning

confidence: 99%

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib

Teng¹,

Oh²,

New³

et al. 2010

Mol Pharmacol

105

138

View full text Add to dashboard Cite

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“…Mechanism-based inhibition (MBI) is a particular issue for the drug-metabolizing cytochrome-P450-dependent enzymes (abbreviated here as CYPs, though there are other cytochrome-P450-dependent enzymes that are not involved in xenobiotic metabolism) [13]. Most enzymes that are targets for drugs have limited substrate specificity.…”

Section: B Mechanism-based Inhibitors (Suicide Inhibitors Suicide Smentioning

confidence: 99%

Covalent Enzyme Inhibition in Drug Discovery and Development

Mehdi

2013

Enzyme Technologies

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Cytochrome P450 Enzymes: A Review on Drug Metabolizing Enzyme Inhibition Studies in Drug Discovery and Development

et al. 2021

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Assessment of drug candidate's potential to inhibit cytochrome P450 (CYP) enzymes remains crucial in pharmaceutical drug discovery and development. Both direct and time-dependent inhibition of drug metabolizing CYP enzymes by the concomitant administered drug is the leading cause of drug–drug interactions (DDIs), resulting in the increased toxicity of the victim drug. In this context, pharmaceutical companies have grown increasingly diligent in limiting CYP inhibition liabilities of drug candidates in the early stages and examining risk assessments throughout the drug development process. This review discusses different strategies and decision-making processes for assessing the drug–drug interaction risks by enzyme inhibition and lays particular emphasis on in vitro study designs and interpretation of CYP inhibition data in a stage-appropriate context.

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Characterization of Cytochrome P450 Mechanism‐Based Inhibition

Cited by 3 publications

References 155 publications

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib

Covalent Enzyme Inhibition in Drug Discovery and Development

Cytochrome P450 Enzymes: A Review on Drug Metabolizing Enzyme Inhibition Studies in Drug Discovery and Development

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