TY - JOUR T1 - Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 753 LP - 761 VL - 20 IS - 5 AU - M Sattler AU - F P Guengerich AU - C H Yun AU - U Christians AU - K F Sewing Y1 - 1992/09/01 UR - http://dmd.aspetjournals.org/content/20/5/753.abstract N2 - The hepatic cytochrome P-450 responsible for metabolism of the structurally related macrolides FK506 and rapamycin in humans was identified using in vitro studies. FK506 and rapamycin metabolism was significantly correlated with nifedipine oxidation in human liver microsomes of eight different individuals. Immunoinhibition with anti-P450 3A4 abolished almost all FK506 and rapamycin metabolite formation. Inactivation of P450 3A4 by incubation of human liver microsomes with triacetyl oleandomycin (50 microM) or gestodene (10 microM) inhibited metabolism of FK506 and rapamycin. In liver microsomes from dexamethasone-treated rats FK506 and rapamycin metabolism was increased compared to liver microsomes from uninduced, phenobarbital-, or 3-methylcholanthrene-induced rats. FK506 and rapamycin were metabolized by reconstituted recombinant human liver P450 3A4. It is concluded that in human and rat liver FK506 and rapamycin are metabolized primarily by cytochrome P-450 3A4. ER -