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British Journal of Anaesthesia, 2001, Vol. 86, No. 4 540-544
© 2001 The Board of Management and Trustees of the British Journal of Anaesthesia

Cytochrome P4502B6 and 2C9 do not metabolize midazolam: kinetic analysis and inhibition study with monoclonal antibodies

N. Hamaoka, Y. Oda, I. Hase and A. Asada

Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno-ku, Osaka 545-8586, Japan*Corresponding author

We determined the contribution of cytochrome P450 (CYP) isoforms to the metabolism of midazolam by kinetic analysis of human liver microsomes and CYP isoforms and by examining the effect of chemical inhibitors and monoclonal antibodies against CYP isoforms in vitro. Midazolam was metabolized to 1'-hydroxymidazolam (1'-OH MDZ) by human liver microsomes with a Michaelis–Menten constant (Km) of 4.1 (1.0) (mean (SD)) µmol litre–1 and a maximum rate of metabolism (Vmax) of 5.5 (1.1) nmol min–1 mg protein–1 (n=6). Of the nine representative human liver CYP isoforms, CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5, three (CYP2B6, 3A4 and 3A5) showed midazolam 1'-hydroxylation activity, with Kms of 40.7, 1.7 and 3.0 µmol litre–1, respectively, and Vmax values of 12.0, 3.3 and 13.2 nmol min–1 nmol P450–1, respectively (n=4). Midazolam 1'-hydroxylation activity of human liver microsomes correlated significantly with testosterone 6ß-hydroxylation activity, a marker of CYP3A activity (r2=0.77, P=0.0001), but not with S-mephenytoin N-demethylation activity, a marker of CYP2B6 activity (r2<0.01, P=0.84) (n=11). Troleandomycin and orphenadrine, chemical inhibitors of CYP isoforms, inhibited the formation of 1'-OH MDZ by human liver microsomes. Monoclonal antibody against CYP3A4 inhibited the formation of 1'-OH MDZ by 79%, whereas monoclonal antibody against CYP2B6 had no effect on midazolam 1'-hydroxylation by human liver microsomes (n=5). These results indicate that only CYP3A4, but not CYP2B6 or CYP2C, is involved in the metabolism of midazolam in vitro.

Br J Anaesth 2001; 86: 540–4


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