Fentanyl inhibits metabolism of midazolam: competitive inhibition of CYP3A4 in vitro

Fentanyl decreases clearance of midazolam administered i.v., but the mechan ism remains unclear. To elucidate this mechanism, we have investigated the effect of fentanyl on metabolism of midazolam using human hepatic microsome s and recombinant cytochrome P450 isoforms (n=6). Midazolam was metabolized to 1'-hydroxymidazolam (1'-OH MDZ) by human hepatic microsomes, with a Mic haelis-Menten constant (K-m) of 5.0 (SD 2.7) mu mol litre(-1). Fentanyl com petitively inhibited metabolism of midazolam in human hepatic microsomes, w ith an inhibition constant (K-i) of 26.8 (12.4) mu mol litre(-1). Of the se ven representative human hepatic P450 isoforms, CYP1A2, 2A6, 2C9, 2C19, 2D6 , 2E1 and 3A4, only CYP3A4 catalysed hydroxylation of midazolam, with a K-m of 3.6 (0.8) mu mol litre(-1). Fentanyl competitively inhibited metabolism of midazolam to 1'-OH MDZ by CYP3A4, with a K-i of 24.2 (6.8) mu mol litre (-1) comparable with the K-i obtained in human hepatic microsomes. These fi ndings indicate that fentanyl competitively inhibits metabolism of midazola m by CYP3A4.