USE OF MIDAZOLAM AS A HUMAN CYTOCHROME-P450-3A PROBE .2. CHARACTERIZATION OF INTERINDIVIDUAL AND INTRAINDIVIDUAL HEPATIC CYP3A VARIABILITY AFTER LIVER-TRANSPLANTATION

Immunosuppression therapy with cyclosporine is often hampered by signi ficant interindividual variability in the metabolic clearance of the d rug. It has been suggested that much of the variability in cyclosporin e clearance is due to differences in the cytochrome P450 3A4 (CYP3A4) content in the liver and intestinal mucosa. A study was conducted in l iver transplant recipients to characterize hepatic CYP3A4 variability during the first 10 days after surgery. The formation of 1'-hydroxymid azolam (1'-OH MDZ) was followed in the plasma after i.v. midazolam (MD Z) administration to 21 multiple-organ donors and to recipients of 10 of the 21 donor livers. Liver biopsy tissue was obtained from donors a nd recipients after the in vivo pharmacokinetic test. For liver donors , the plasma 1'-OH MDZ/MDZ concentration ratio 30 min after the i.v. M DZ dose was well correlated with the hepatic CYP3A4 content (r = .87, P < .001). Much of the variability in the two parameters was attribute d to the administration of enzyme-inducing drugs before organ procurem ent. The mean hepatic CYP3A4 content and plasma 1'-OH MDZ/MDZ concentr ation ratio in six inducer-treated donors was 4.7-fold and 2.3-fold hi gher than the respective mean value for all other donors. The hepatic CYP3A4 content and plasma 1'-OH MDZ/MDZ ratio for liver recipients, st udied on postoperative day 10, was negatively correlated with the resp ective parameter measured in donors on day 0 (r = -0.60 for CYP3A4 and r = -0.79 for 1'-OH MDZ/MDZ; P < .05 and P < .01). The dynamic change s in hepatic CYP3A4 expression during the perioperative period, some o f which appear to be due to the effect of enzyme-inducing drugs, help explain the difficulties often encountered in the achievement and main tenance of therapeutic cyclosporine blood levels after liver transplan tation.