PP144—Assessing In Vivo Enzyme Genetic Variation in the Presence of Transporter Effect

Abstract

PP144—ASSeSSiNg iN ViVo eNzyme geNeTiC VAriATioN iN The PreSeNCe of TrANSPorTer effeCT R. Chauhan; N. Tsamandouras; and A. Rostami-Hodjegan School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester; and Simcyp Ltd, Sheffield, United Kingdom Introduction: Interindividual variability in drug efficacy and toxicity can be partly attributed to genetic variation in metabolic enzymes, such as CYP2D6. The administration of probe substrates such as debrisoquine has been widely used in vivo to phenotype CYP2D6 metabolic activity. Recently, it was revealed that debrisoquine is also a substrate for the OCT1 uptake transporter. Therefore, the principal focus of this study was to analyze the misphenotyping that may arise in the complex situation, where drugs are substrates to both polymorphic enzymes and hepatic uptake transporters. Patients (or Materials) and Methods: A physiologically based pharmacokinetic modeling and simulation approach was carried out using the Simcyp Simulator (v12). A virtual study population (n = 1000) was generated including extensive, poor, and ultrarapid CYP2D6 metabolizers (86.5%, 8.2%, and 5.3% of the population, respectively). CYP2D6 activity was phenotyped using dextromethorphan as a probe substrate and monitoring indirect metrics such as the urinary recovery or plasma area under the curve metabolite/drug (dextrorphan/dextromethorphan) ratios. Multimodality in the frequency distribution of these metrics in the study population was assessed with the NTV (normal test variable) graphical method. Using a permeability-limited liver model and gradually decreasing the influx of the probe substrate into the liver, we investigated the effects of this decrease on the modality of the metrics frequency distribution. Results: Phenotyping successfully identified a clear multimodal frequency distribution in the study population with regard to CYP2D6 activity, when no hepatic permeability restrictions are applied to the probe substrate. However, when the uptake of the probe substrate into the liver is not passive but mainly transporter-mediated, the multimodality on the frequency distribution was clearly affected, confounding the distinction between the poor and extensive metabolizers. Specifically, when the contribution of the active uptake to total uptake was > 90%, multimodality was distorted to a unimodal frequency distribution. Conclusion: In conclusion, the findings suggest that when using a probe drug to phenotype the activity of a metabolic enzyme the hepatic permeability characteristics of the compound should be also considered. When uptake of the probe drug is predominately transporter mediated, influx into hepatocytes and not metabolism is the step that mostly contributes to the phenotype. Taking also into account that uptake transporters can also be polymorphically expressed the possibility that transporter variation can produce a flawed perception of enzyme activity should not be neglected. Disclosure of Interest: None declared.