Fig. 2.

CYP3A5 is the primary enzyme responsible for M1 formation. A, a panel of cDNA-expressed P450s was incubated with maraviroc followed by metabolite analysis. B, ketoconazole inhibited M1 formation. P450 chemical inhibitors were preincubated with human liver microsomes before the addition of maraviroc. The data are presented as percentage M1 formation activity remaining relative to vehicle control. The P450 targeted by the particular chemical inhibitor is shown at the top of the figure. ***, P < 0.001 compared with solvent control. C, M1 formation rate by CYP3A5 is greater than that by CYP3A4. cDNA-expressed CYP3A4 and CYP3A5 were incubated with 0.1 to 1000 μM maraviroc under initial rate conditions. M1 formation was determined using a maraviroc standard curve and maraviroc-d₆ as an internal standard. Kinetics data at maraviroc concentrations in the therapeutic range are shown in the inset. PPP, 2-phenyl-2-(1-piperidinyl) propane.