The effect of eight drugs on the metabolism of FK506 (tacrolimus) by human liver microsomes was studied at a substrate concentration of 10 microM. NADPH-dependent oxidative metabolism of FK506 was inhibited 20, 15, and 10% by quinidine, omeprazole, and sulindac, respectively, at 100 microM. Theophylline, diclofenac, indomethacin, phenylbutazone, and cimetidine (at ten times molar excess of FK506) and all eight drugs (at equal molar concentration) had slight effects on metabolism. The effects of these drugs were much weaker than that of cyclosporin A. The effect of FK506 on NADPH-dependent oxidation of prednisolone and theophylline by human liver microsomes were also studied. FK506 inhibited prednisolone metabolism in a concentration-dependent manner but exhibited a negligible effect on theophylline metabolism. The results suggest potential for interactions between FK506 and drugs metabolized by the cytochrome P450 3A subfamily.