Role of CYP3A enzymes in fluticasone biotransformation

Abstract

Fluticasone propionate (FLU) is a synthetic, trifluorinated glucocorticoid with potent anti-inflammatory action that is commonly used in patients with asthma. After oral or intranasal administration, FLU undergoes rapid hepatic inactivation to a single metabolite, a 17β-carboxylic acid derivative (M1). M1 formation has been attributed largely to cytochrome P450 (CYP) 3A4, however, there are no published data that confirm this assertion. Hence, in vitro studies were conducted to determine the role that human CYPs play in the metabolism of FLU. Consistent with in vivo data, human liver microsomes (HLM) catalyzed the formation of a single metabolite (M1) at low substrate concentrations (<1 μM; mean plasma Cmax = 1 nM). At FLU concentrations <1 μM, the kinetics of M1 formation in HLM were consistent with those of a single enzyme (Km ≅800 nM). M1 formation correlated significantly (r>0.95) with CYP3A4/5 activities in a panel of HLM (n=14) and was markedly impaired by the CYP3A inhibitor, ketoconazole, (>94%), but not by inhibitors of other CYPs (<10%). Studies with a panel of cDNA-expressed enzymes revealed that M1 formation was catalyzed solely by CYP3A enzymes at FLU concentrations <1 μM. M1 formation was catalyzed by CYPs 3A4, 3A5 and 3A7, however CYP3A5 was ~4-fold less active than CYP3A4 or 3A7. These results suggest that at pharmacologically relevant concentrations of FLU, biotransformation of FLU to M1 is mediated predominantly by CYPs 3A4 and 3A7. Clinical Pharmacology & Therapeutics (2004) 75, P84–P84; doi: 10.1016/j.clpt.2003.11.320