Characterization of Cytochrome<scp>P</scp>450 Mechanism‐Based Inhibition

Rock, Dan A.; Wienkers, Larry C.

doi:10.1002/9780470571224.pse117

Cited by 3 publications

(3 citation statements)

References 157 publications

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“…For this reason, not all predicted drug-drug interactions will be clinically significant. (2) Secondly, the partition ratio alters the balance of MBI and of the amount of reactive metabolite released for binding to other hepatic proteins (Rock, 2010). This ratio is a quantitative guide that defines the likelihood of inhibition and should be discussed in conjunction with the actual presentation of the drug to CYP450 enzymes for metabolism.…”

Section: Section 6: Future Perspectivementioning

confidence: 99%

“…tight, but reversible in vitro ) to the prosthetic heme iron via a coordinate bond or a metabolite-intermediate (MI) complex. Each of these mechanisms sets up a unique biochemical signature that can be experimentally differentiated; while all three subtypes demonstrate time-dependent inhibition, alkylation of the porphyrin ring tends to generate a reduction in the carbon monoxide (CO)-CYP450 differential spectrum (Rock, 2010), while formation of an MI complex produces a characteristic spectrum in the Soret region (400–500 nm), which can be reversed by the addition of ferricyanide (Riley et al, 2007). Regardless of these subtle differences, these inactivation processes arise from the initial metabolism of the substrate, alluding to a profound specificity and an increased risk that the resulting reactive metabolite will bind within the active site (Ortiz de Montellano, 2005).…”

Section: Section 1: Introduction To Mechanism-based Inactivation Of Cmentioning

confidence: 99%

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Mechanism-based inactivation of CYP450 enzymes: a case study of lapatinib

Chan

Hardy

et al. 2015

Drug Metabolism Reviews

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Mechanism-based inactivation (MBI) of CYP450 enzymes is a unique form of inhibition in which the enzymatic machinery of the victim is responsible for generation of the reactive metabolite. This precondition sets up a time-dependency for the inactivation process, a hallmark feature that characterizes all MBI. Yet, MBI itself is a complex biochemical phenomenon that operates in different modes, namely covalent binding to apoprotein, covalent binding of the porphyrin group, and also complexation of the catalytic iron. Using lapatinib as a recent example of toxicological interest, we present an example of a mixed-function MBI that can confound clinical drug-drug interactions manifestation. Lapatinib exhibits both covalent binding to the apoprotein, and formation of a metabolite-intermediate (MI) complex in an enzyme-selective manner (CYP3A4 versus CYP3A5), each with different reactive metabolites. The clinical implication of this effect is also contingent upon genetic polymorphisms of the enzyme involved as well as the co-administration of other substrates, inhibitors or inducers, culminating in drug-drug interactions. This understanding recapitulates the importance of applying isoform-specific mechanistic investigations to develop customized strategies to manage such outcomes.

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Section: Section 6: Future Perspectivementioning

confidence: 99%

Section: Section 1: Introduction To Mechanism-based Inactivation Of Cmentioning

confidence: 99%

Mechanism-based inactivation of CYP450 enzymes: a case study of lapatinib

Chan

Hardy

et al. 2015

Drug Metabolism Reviews

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“…These include clinically important interactions between CYP2C8 substrates and heart disease medications gemfibrozil and clopidogrel, due to time-dependent inhibition or mechanism-based inactivation of CYP2C8 by the acyl β– d –glucuronide (acyl glucuronide) metabolites of these drugs [ 11 , 13 , 14 ]. There are at least four known mechanisms of CYP inactivation namely heme alkylation, protein alkylation, formation of a metabolic intermediate complex and heme bleaching or destruction [ 1 , 15 ]. Mechanism-based inhibition involves the irreversible inhibition and inactivation of the enzyme via the formation of a reactive intermediate which binds to and alters the enzyme’s function or metabolism of drug substrates.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of CYP2C8 by Acyl Glucuronides of Gemfibrozil and Clopidogrel: Pharmacological Significance, Progress and Challenges

Shah

2022

Biomolecules

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The lipid-regulating drug gemfibrozil is a useful medication for reducing high cholesterol and triglycerides in the blood. In addition to oxidation, it undergoes extensive glucuronidation to produce gemfibrozil acyl glucuronide, which is a known mechanism-based inactivator of cytochrome P450 (CYP) 2C8. Such selective and time-dependent inhibition results in clinically important drug–drug interactions (DDI) with the drugs metabolized by CYP2C8. Similarly, the acyl glucuronide of clopidogrel, a widely used antiplatelet agent, is a potent time-dependent inhibitor of CYP2C8 that demonstrated significant DDI with the substrates of CYP2C8. Current progress in atomic-level understanding mostly involves studying how different drugs bind and undergo oxidation in the active site of CYPs. It is not clear how an acyl glucuronide metabolite of the drug gemfibrozil or clopidogrel interacts in the active site of CYP2C8 and selectively inhibit the enzyme. This mini-review summarizes the current knowledge on some of the important clinical DDI caused by gemfibrozil and clopidogrel due to the inhibition of CYP2C8 by acyl glucuronide metabolites of these drugs. Importantly, it examines recent developments and potential applications of structural biology tools to elucidate the binding and orientation of gemfibrozil acyl glucuronide and clopidogrel acyl glucuronide in the active site near heme that contributes to the inhibition and inactivation of CYP2C8.

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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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Characterization of CytochromeP450 Mechanism‐Based Inhibition

Cited by 3 publications

References 157 publications

Mechanism-based inactivation of CYP450 enzymes: a case study of lapatinib

Mechanism-based inactivation of CYP450 enzymes: a case study of lapatinib

Inhibition of CYP2C8 by Acyl Glucuronides of Gemfibrozil and Clopidogrel: Pharmacological Significance, Progress and Challenges

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib

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