Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Kaspera, R; Kirby, BJ; Sahele, T; Collier, AC; Kharasch, ED; Unadkat, JD; Totah, RA

Published Date

  • September 1, 2014

Published In

Volume / Issue

  • 91 / 1

Start / End Page

  • 109 - 118

PubMed ID

  • 24973543

Pubmed Central ID

  • PMC4169885

Electronic International Standard Serial Number (EISSN)

  • 1873-2968

Digital Object Identifier (DOI)

  • 10.1016/j.bcp.2014.06.020


  • eng

Conference Location

  • England