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Pharmacogenetics
Simcyp allows you to assess the likely impact of genetic polymorphisms in CYP and UGT enzymes on the pharmacokinetics of new chemical entities.
The Simcyp databases contain genetic information on different populations. Phenotype frequencies, derived from comprehensive meta-analyses, are used to simulate populations with representative numbers of poor metabolisers (PMs) with respect to polymorphic CYPs (e.g. CYP2D6).
In the case of CYP2C9, which has allelic variants with markedly decreased activity compared to wild-type, information on specific genotypes is embedded in the algorithm. On this basis, it has been possible, for example, to use in vitro data on the metabolism of S-warfarin and tolbutamide by the different variants (Figure 8) to predict in vivo clearances in the various genotypes (Almond et al., 2006a; Almond et al., 2006b).
Figure 8. A comparison of observed oral clearances (CLpo) of tolbutamide in different CYP2C9 genotypes with those predicted from in vitro data using Simcyp. Predicted and observed variability is also indicated.
In further developments, Simcyp is linking genetic variability in enzymes to predict pharmacodynamic outcome [Dickinson et al., 2006a; Dickinson et al., 2006b].
