Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate?

Dorne, Jean‐Lou; Walton, K; Slob, Wout; Renwick, A.G.

doi:10.1016/s0278-6915(02)00117-5

Cited by 61 publications

(57 citation statements)

References 117 publications

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“…The primarily hepatic expression of this enzyme governs first pass metabolism after oral drug administration, whereas the low levels of intestinal expression do not appear to be important (Madani et al, 1999). Numerous studies have characterized the impact of CYP2D6 polymorphism on substrate area under the curve (AUC) in EM and PM subjects, and a recent article by Dorne et al (2002) provides a useful database of human clearance and metabolite recovery data.Because the safety profile of a new discovery candidate is often unknown, it is beneficial to limit the contribution of polymorphic enzymes below some cutoff to avoid the requirement of phenotyping/ genotyping before the initiation of drug therapy and distinct dosing regimens in EM and PM subjects. A variety of in vitro tools are available to determine the relative contribution or percent contribution to metabolism by a polymorphic enzyme.…”

mentioning

confidence: 99%

Minimizing Polymorphic Metabolism in Drug Discovery: Evaluation of the Utility of in Vitro Methods for Predicting Pharmacokinetic Consequences Associated with CYP2D6 Metabolism

Gibbs

Hyland²,

Youdim³

2006

Drug Metab Dispos

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ABSTRACT:Minimizing interindividual variability in drug exposure is an important goal for drug discovery. The reliability of the selective CYP2D6 inhibitor quinidine was evaluated in a retrospective analysis using a standardized approach that avoids laboratory-to-laboratory variation. The goal was to evaluate the reliability of in vitro metabolism studies for predicting extensive metabolizer (EM)/poor metabolizer (PM) exposure differences. Using available literature, 18 CYP2D6 substrates were selected for further analysis. In vitro microsomal studies were conducted at 1 M substrate and 0.5 M P450 to monitor substrate depletion. An estimate of the fraction metabolized by CYP2D6 in microsomes was derived from the rate constant determined with and without 1 M quinidine for 11 substrates. Clearance in EM and PM subjects and fractional recovery of metabolites were taken from the literature. A nonlinear relationship between the contribution of CYP2D6 and decreased oral clearance for PMs relative to EMs was evident. For drugs having <60% CYP2D6 involvement in vivo, a modest difference between EM and PM exposure was observed (<2.5-fold). For major CYP2D6 substrates (>60%), more dramatic exposure differences were observed (3.5-to 53-fold). For compounds primarily eliminated by hepatic P450 and with sufficient turnover to be evaluated in vitro, the fraction metabolized by CYP2D6 in vitro compared favorably with the in vivo data. The in vitro estimation of fraction metabolized using quinidine as a specific inhibitor provided an excellent predictive tool. Results from microsomal substrate depletion experiments can be used with confidence to select compounds in drug discovery using a cutoff of >60% metabolism by CYP2D6.Minimizing interindividual variability in drug exposure is an important goal in drug discovery. One major source of interindividual variability in drug exposure involves clearance. The variable expression of drug-metabolizing enzymes can result in profound differences in drug exposure across a patient population. The genetic basis for interindividual variability has been described for numerous drugmetabolizing enzymes. Some common examples of polymorphic drug-metabolizing enzymes include thiopurine methyltransferase, glutathione S-transferase M1-1, CYP2C9, CYP2C19, CYP2D6, CYP3A5, N-acetyltransferase 1, UGT1A1, and flavin monooxygenase 3 (Haining and Yu, 2003).The consequences of polymorphic enzymes on drug metabolism in relation to efficacy and side effects has been the focus of numerous studies (Vandel et al., 1999;Dandara et al., 2001). For instance, individuals lacking the expression of a polymorphic drug-metabolizing enzyme (commonly referred to as "poor metabolizers" or PMs) will have higher drug exposure if those drugs are metabolized by those polymorphic enzymes, which could lead to exaggerated pharmacology or enhanced side effects relative to the intermediate metabolizer and extensive metabolizer (EM) subjects given the same dose (Mahgoub et al., 1977). Alternatively, if a polymorphic enzyme forms a p...

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mentioning

confidence: 99%

Minimizing Polymorphic Metabolism in Drug Discovery: Evaluation of the Utility of in Vitro Methods for Predicting Pharmacokinetic Consequences Associated with CYP2D6 Metabolism

Gibbs

Hyland²,

Youdim³

2006

Drug Metab Dispos

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“…Defining the changes seen in drug efficacy and toxicity are of crucial significance since PK measurements alone cannot explain such variability (Kuehl P, 2001;Evans WE, 1999;Kroetz DL, 2003;Lai Y, 2011). The intrapatient variability and large population differences suggest that genetic inheritance may be a critical determinant of the therapeutic responses to drugs which are substrates for ABC-transporters and CYP450 enzymes (Ameyaw MM, 2001;Dorne JL, 2002;Evans WE, 2001). Although we know many nongenetic (or epigenetic) factors influence the effects of medications, including age, organ function, concomitant therapy, drug interactions and the nature of the disease, there are now numerous examples of cases in which interindividual differences in drug response are attributed to sequence variants in genes encoding drug-metabolizing enzymes and drug transporters.…”

Section: Pharmacogenomicsmentioning

confidence: 99%

“…Although some studies suggest that CYP-mediated activity and enzyme affinity for their substrates are not altered during the aging process, clinically relevant changes in drug-metabolizing enzyme expression have been observed. For instance, a clear age-related decline (20%) in the metabolism of CYP2D6 substrates has been demonstrated (Corsonello et al 2010;Dorne et al, 2002;O'Connell et al, 2006). Selective serotonin reuptake inhibitors (SSRIs) can inhibit CYP2D6 activity and therefore reduce the efficiency of drugs that need to be activated by CYP2D6 when coadministered, such as tamoxifen and codeine.…”

Section: Drug Disposition: Effects Age Sex and Ethnicitymentioning

confidence: 99%

Pharmacogenomics Dictate Pharmacokinetics: Polymorphisms in Drug-Metabolizing Enzymes and Drug-Transporters

Mondal¹,

Gerlach²,

Datta³

et al. 2012

Readings in Advanced Pharmacokinetics - Theory, Methods and Applications

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“…There is wide inter-individual variation in polymorphic pathways of metabolism, for example CYP2D6, CYP2C19 and N-acetyl transferase-2 (Dorne et al, 2002 and2003;Knudsen et al, 2001;Vineis et al, 2001). Differences between extensive metabolisers (EM) and poor metabolisers (PM) for substrates of CYP2D6 and CYP2C19 can greatly exceed the default uncertainty factor of 3.16 or 10 0.5 , which normally allows for human variability in kinetics (Dorne et al, 2002 and2003). In the case of CYP2D6 the difference in internal dose between EM and PM subjects may exceed 30-fold if the substance is metabolised exclusively by CYP2D6, but the difference would be only about 2-fold if CYP2D6 was responsible for the elimination of 10% or less of the compound (Dorne et al, 2002).…”

Section: Consideration Of Individuals With High Susceptibilitymentioning

confidence: 99%

“…Differences between extensive metabolisers (EM) and poor metabolisers (PM) for substrates of CYP2D6 and CYP2C19 can greatly exceed the default uncertainty factor of 3.16 or 10 0.5 , which normally allows for human variability in kinetics (Dorne et al, 2002 and2003). In the case of CYP2D6 the difference in internal dose between EM and PM subjects may exceed 30-fold if the substance is metabolised exclusively by CYP2D6, but the difference would be only about 2-fold if CYP2D6 was responsible for the elimination of 10% or less of the compound (Dorne et al, 2002). Replacement of the default factor of 3.16 by a CSAF (see Edler et al, 2002) for human variability requires selection of a percentage of the population that the CSAF would cover.…”

Section: Consideration Of Individuals With High Susceptibilitymentioning

confidence: 99%

Risk characterisation of chemicals in food and diet

Renwick

Barlow

Hertz‐Picciotto

et al. 2003

Food and Chemical Toxicology

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167

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Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate?

Cited by 61 publications

References 117 publications

Minimizing Polymorphic Metabolism in Drug Discovery: Evaluation of the Utility of in Vitro Methods for Predicting Pharmacokinetic Consequences Associated with CYP2D6 Metabolism

Minimizing Polymorphic Metabolism in Drug Discovery: Evaluation of the Utility of in Vitro Methods for Predicting Pharmacokinetic Consequences Associated with CYP2D6 Metabolism

Pharmacogenomics Dictate Pharmacokinetics: Polymorphisms in Drug-Metabolizing Enzymes and Drug-Transporters

Risk characterisation of chemicals in food and diet

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