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.

Danazol Inhibits Cytochrome P450 2J2 Activity in a Substrate-independent Manner

“…Recent studies report that CYP2J2 also plays a role in the biotransformation of xenobiotics, including drugs such as albendazole (Wu et al, 2013b), astemizole (Matsumoto et al, 2002), apixaban (Wang et al, 2010), ebastine (Liu et al, 2006), fenbendazole (Wu et al, 2013b), ritonavir (Kaspera et al, 2014), and terfenadine (Lafite et al, 2006). Using strong chemical inhibitors to inhibit the biotransformation activity of recombinant P450 isoforms or human liver microsomes is a valuable method for P450 reaction phenotyping studies to characterize the enzymes responsible for drug metabolism (Rodrigues, 1999;Yoon and Liu, 2011).…”

Characterization of Atomoxetine Biotransformation and Implications for Development of PBPK Models for Dose Individualization in Children

“…Heterologously expressed enzyme CYP2J2 was the only CYP, other than CYP2D6, to form 4-OH-ATX, albeit with rates 100-fold lower than CYP2D6. Hepatic abundance of CYP2J2 is low, but its importance may be relevant in individuals who have low CYP2D6 activity, as with the anti-viral drug ritonavir (Kaspera et al, 2014). Studies using specific chemical inhibitors of CYPs in the HLM sample genotyped as an intermediate metabolizer (AS = 0.5) found that CYP2D6 and CYP2E1 were the major isoforms involved in 4-OH-ATX formation.…”

The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral‐mediated drug–drug interactions on piperaquine antimalarial therapy during pregnancy

“…Efavirenz and ritonavir are pre‐validated compounds developed by Simcyp and included in the Simcyp Simulator® compound library. The ritonavir compound file has been widely used as a CYP3A4 inhibitor in mechanistic modelling (Colbers, Greupink, Litjens, Burger, & Russel, ; Hyland, Dickins, Collins, Jones, & Jones, ; Kaspera et al, ; Marsousi et al, ; Wang, ), and compound‐specific parameters and validation data for the use of efavirenz as a CYP3A4 and 2B6 inducer within the Simcyp Simulator®, have recently been published (Ke, Barter, Rowland‐Yeo, & Almond, ).…”