Abstract

In vitro microsomal formation of primary metabolites of indinavir (CRIXIVAN, MK-0639, L-735,524), an HIV protease inhibitor, were qualitatively similar among the different developmental stages in humans, although the fetal liver had a lower capability to form the metabolites than the pediatric and adult liver. The lower activity of fetal liver was mainly owing to a decrease in theV_max values. TheV_max value in the fetus was about one-third of that in the adult human, while no significant difference was found in K_m values between groups. The liver microsomes were also characterized using P450 markers to examine the development-associated alteration in P450 functional activities. Debrisoquine 4-hydroxylase activity was comparable among the three age groups. In contrast, tolbutamide methyl hydroxylase activity, as well as the CYP3A marker, testosterone 6β-hydroxylase activity, in the fetal liver microsomes was much lower than in the pediatric and adult by more than 40-fold. However, the difference in testosterone 2β-hydroxylase and nifedipine N-oxidase activities between fetus and adult was markedly smaller. The ratio of indinavir metabolism in pediatric or adult liver to fetus was 1.7 for pediatric and 3.6 for adult liver microsomes. Similarly, testosterone 2β-hydroxylase and nifedipine N-oxidase activities showed smaller differences between adult (or pediatric) and fetal liver microsomes than testosterone 6β-hydroxylase activity. The reason for the observed marked differences in the development-associated alteration may lie in the differences of substrate specificities between CYP3A isoforms.