Vol. 31, Issue 3, 275-281, March 2003

Oxidative Metabolism of Amprenavir in the Human Liver. Effect of the CYP3A Maturation

J. M. Tréluyer, G. Bowers, N. Cazali, M. Sonnier, E. Rey, G. Pons, and T. Cresteil

Pharmacologie Périnatale et Pédiatrique, Hôpital Saint Vincent de Paul, Paris, France (J.M.T., N.C., E.R., G.P.); GlaxoSmithKline, Research Triangle Park, North Carolina (G.B.); and Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique Unité Propre de Recherche 2301, Gif sur Yvette, France (M.S., T.C.)

Amprenavir is a human immunodeficiency virus-1 (HIV-1) protease inhibitor intended to be used to treat HIV-infected children. Although a pediatric dosage is proposed by the manufacturer, no data are currently available on the pharmacokinetics of amprenavir in neonates and infants. Amprenavir being primarily eliminated after oxidative biotransformation, we explored its in vitro metabolism by cytochrome P450 (P450)-dependent monooxygenases. In our conditions, five metabolites were formed in vitro and subsequently analyzed by liquid chromatography-mass spectrometry; P450-dependent oxidations occurred either on the tetrahydrofuran ring (M3 and M4), the aniline ring (M5), and the aliphatic chain (M2) or resulted from the N-dealkylation and loss of the tetrahydrofuran ring (M1). The two major metabolites, respectively M3 and M2 were formed by human liver microsomes with K_m between 10 and 70 µM. CYP3A4 and to a lesser extent CYP3A5 were major contributors for the formation of M2, M3, and M5 metabolites, whereas CYP3A7 had no or little activity. This assumption was confirmed by inhibition with ketoconazole and ritonavir (two potent inhibitors of CYP3A) whereas sulfaphenazole (2C9 inhibitor) and quinidine (2D6 inhibitor) were inefficient. The metabolism of amprenavir was negligible in microsomes from either fetuses or neonates and steadily increased after the first weeks of life in relation with the maturation of CYP3A4/5. In conclusion, results demonstrated that the capacity of the human liver to oxidize amprenavir is low during the first weeks after birth and that dosage could be substantially reduced during the early neonatal period.