Differential inhibition of cytochromes P450 3A4 and 3A5 by the newly synthesized coumarin derivatives 7-coumarin propargyl ether and 7-(4-trifluoromethyl)coumarin propargyl ether.

The abilities of 7-coumarin propargyl ether (CPE) and 7-(4-trifluoromethyl)coumarin propargyl ether (TFCPE) to act as mechanism-based inactivators of P450 3A4 and 3A5 in the reconstituted system have been investigated using 7-benzyloxy-4-(trifluoromethyl)coumarin (BFC) and testosterone as probes. CPE inhibited the BFC O-debenzylation activity of P450 3A4 in a time-, concentration-, and NADPH-dependent manner characteristic of a mechanism-based inactivator with a half-maximal inactivation (K(I)) of 112 microM, a maximal rate of inactivation (k(inact)) of 0.05 min(-1), and a t(1/2) of 13.