title: Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo.
abstract: Ritonavir, an HIV protease inhibitor, is successfully used for the prevention and treatment of HIV infections. Ritonavir pharmacokinetics are complicated by inhibition, induction and pharmacogenetics of cytochrome P450 (CYP) enzymes mediating its clearance. This investigation revealed that CYP2J2, along with CYP3A4/5 and CYP2D6, efficiently metabolizes ritonavir, and to a CYP2J2-specific (minor) metabolite. Chemical inhibition of ritonavir metabolism, clearance, KI/kinact and abundance of CYP2J2 in liver microsomes were evaluated and then applied to an in vitro-in vivo static scaling model to estimate the contribution of each isozyme, as a function of CYP abundance, activity, and genotype. Disposition of the CYP2J2-specific metabolite was also evaluated in vivo. In plasma, metabolite abundance was well above previously reported levels with circulating concentrations measured at 2 μM for the main hydroxylisopropyl metabolite. Ritonavir and metabolite plasma profiles were simulated using Simcyp(®). A modest (2-6%) contribution of CYP2J2 to ritonavir clearance is predicted which increases to more than 20% in subjects carrying CYP2D6 poor metabolizer polymorphisms and CYP3A4 irreversible inhibition. These results indicate that minor drug metabolizing enzymes could become quantitatively important in RTV clearance if main metabolic pathways are impeded.
authors: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Box 357610, Seattle, WA 98195-7610, USA. Electronic address: kaspera@uw.edu.
authors: Rüdiger
authors: R
authors: Kaspera
authors: Department of Pharmaceutics, School of Pharmacy, University of Washington, Box 357630, Seattle, WA 98195-7630, USA. Electronic address: brian.kirby@gilead.com.
authors: Brian J
authors: BJ
authors: Kirby
authors: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Box 357610, Seattle, WA 98195-7610, USA. Electronic address: tarikucs@gmail.com.
authors: Tariku
authors: T
authors: Sahele
authors: Department of Medicine, University of Washington, Box 359929, Seattle, WA 98195-9929, USA. Electronic address: acollier@u.washington.edu.
authors: Ann C
authors: AC
authors: Collier
authors: Department of Anesthesiology, School of Medicine, Washington University, 660 South Euclid Avenue, Campus Box 8054, St. Louis, MO 63110, USA. Electronic address: kharasch@wustl.edu.
authors: Evan D
authors: ED
authors: Kharasch
authors: Department of Pharmaceutics, School of Pharmacy, University of Washington, Box 357630, Seattle, WA 98195-7630, USA. Electronic address: jash@uw.edu.
authors: Jashvant D
authors: JD
authors: Unadkat
authors: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Box 357610, Seattle, WA 98195-7610, USA. Electronic address: rtotah@uw.edu.
authors: Rheem A
authors: RA
authors: Totah
mesh_terms: D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D008658:Inactivation, Metabolic; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D019438:Ritonavir / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: C000717350:CYP2J2 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D019438:Ritonavir
keywords: CYP2D6; CYP2J2; CYP3A4; In vivo; Ritonavir; Simcyp; Time dependent inhibition