THE PROPERTY OF EXPRESSED CYP2D6*10 AND ITS POSSIBILITY AS A TOOL FOR PREDICTING HUMAN PHARMACOKINETICS

Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O-desmethylvenlafaxine (ODV). We have found that the CYP2D6*10 genotype influenced the pharmacokinetics of venlafaxine in Japanese population. We have recently expressed the CYP2D6*10A, *10C, *1(wild) and other two variants in yeast cell. The CO-reduced difference spectra of the variants conteining amino acid substitution Pro34->Ser resulted in a dominant absorption at 420nm as well as 450nm, suggesting that the substitution caused a unstabl form proteine. In addition, exchange of the proline residue to serine at same position in rat CYP2D1 also increased P420, denatured P450. The apparent Km values of CYP2D6* 10A, CYP2D6* 10C and CYP2D6* 1(wild) for bufuralol 1'-hydroxylation were 6.39, 63.1 and 1.31μM, and for venlafaxine O-demethylation 83.6, 82.2 and 9.91 p.M, respectively. These findings suggest that the decreased disposition of venlafaxine in vivo was caused not only instability but also increased Km value of CYP2D6* 10. We proposed that these enzymes in vitro may be used as a tool for predicting the effect of the CYP2D6*10 genotypes on human in vivo pharmacokinetics.