ArticleDrug metabolism and disposition: the biological fate of chemicals2013
The effect of ritonavir on human CYP2B6 catalytic activity: heme modification contributes to the mechanism-based inactivation of CYP2B6 and CYP3A4 by ritonavir.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- Interaction of CYP3A4 with the inhibitor cobicistat: Structural and mechanistic insights and comparison with ritonavir.Archives of biochemistry and biophysics · 2024Article
- The inhibitory and inducing effects of ritonavir on hepatic and intestinal CYP3A and other drug-handling proteins.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2023Review
- The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?International journal of molecular sciences · 2022Review
- Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.International journal of molecular sciences · 2022Article
- Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength.International journal of molecular sciences · 2021Article
- Article
- Formation of Both Heme and Apoprotein Adducts Contributes to the Mechanism-Based Inactivation of Human CYP2J2 by 17Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Inhibition of Human CYP3A4 by Rationally Designed Ritonavir-Like Compounds: Impact and Interplay of the Side Group Functionalities.Molecular pharmaceutics · 2018Article
- Heme Modification Contributes to the Mechanism-Based Inactivation of Human Cytochrome P450 2J2 by Two Terminal Acetylenic Compounds.Drug metabolism and disposition: the biological fate of chemicals · 2017Article
- Pharmacogenetic Associations with ADME Variants and Virologic Response to an Initial HAART Regimen in HIV-Infected Women.International journal of HIV/AIDS and research · 2017Article
- Structure-Based Inhibitor Design for Evaluation of a CYP3A4 Pharmacophore Model.Journal of medicinal chemistry · 2016Article
- Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- Kinetics of cytochrome P450 3A4 inhibition by heterocyclic drugs defines a general sequential multistep binding process.The Journal of biological chemistryArticle
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The mechanism-based inactivation of human CYP2B6 by ritonavir (RTV) in a reconstituted system was investigated. The inactivation is time, concentration, and NADPH dependent and exhibits a K(I) of 0.9 μM, a k(inact) of 0.05 min⁻¹, and a partition ratio of approximately 3. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that the protonated molecular ion of RTV exhibits an m/z at 721 and its two major metabolites are an oxidation product with MH⁺ at m/z 737 and a deacylated product with MH⁺ at m/z 580. Inactivation of CYP2B6 by incubation with 10 μM RTV for 10 min resulted in an approximately 50% loss of catalytic activity and native heme, but no modification of the apoprotein was observed. RTV was found to be a potent mixed-type reversible inhibitor (K(i) = 0.33 μM) and a type II ligand (spectral dissociation constant-K(s) = 0.85 μM) of CYP2B6. Although previous studies have demonstrated that RTV is a potent mechanism-based inactivator of CYP3A4, the molecular mechanism responsible for the inactivation has not been determined. Here, we provide evidence that RTV inactivation of CYP3A4 is due to heme destruction with the formation of a heme-protein adduct. Similar to CYP2B6, there is no significant modification of the apoprotein. Furthermore, LC-MS/MS analysis revealed that both CYP3A4 and human liver microsomes form an RTV-glutathione conjugate having a MH⁺ at m/z 858 during metabolism of RTV, suggesting the formation of an isocyanate intermediate leading to formation of the conjugate.
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