Pharmacokinetic-pharmacogenetic modelling in the detection of polymorphisms in xenobiotic metabolism

Study of the genetic control of xenobiotic metabolism is hindered in the areas of detecting new polymorphisms and estimating the frequency and enzyme activity of each phenotype. Using computer simulation we have looked at pharmacogenetic-pharmacokinetic models based on two alleles under Hardy-Weinberg equilibrium. The distributions of the area under the concentration-time curve (AUC) or urinary ratios were modelled and the effects of incomplete urine collections, sequential, parallel and non-linear pathways investigated. The statistical methods for the detection of bimodality in these distributions were explored. The drug/metabolite ratio, which has a good theoretical basis, was confirmed to be most sensitive and robust to changes in bioavailability, urinary excretion, hepatic blood flow and variation in non-polymorphic enzyme activity but not parallel, sequential or non-linear routes of metabolism. Graphical methods, while able to illustrate deviations from normality, were not specific in detecting bimodality and the hypothesis testing methods were found to be heavily dependent upon their assumptions.