ReviewInternational journal of molecular sciences2022
The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?
Review in International journal of molecular sciences, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
63 citing papers in PubMed, 114 citations in OpenAlex.
- Model-based evaluation of the interaction between ritonavir-boosted atazanavir and rifampicin in Ugandan adults with HIV.British journal of clinical pharmacology · 2025Trial
- Model-informed drug development in public health emergency of international concern: accelerating marketing authorization of simnotrelvir.Antimicrobial agents and chemotherapy · 2025Trial
- Single- and multiple-dose pharmacokinetics and safety of the SARS-CoV-2 3CL protease inhibitor RAY1216: a phase 1 study in healthy participants.Antimicrobial agents and chemotherapy · 2025Trial
- Time Course of the Interaction Between Oral Short-Term Ritonavir Therapy with Three Factor Xa Inhibitors and the Activity of CYP2D6, CYP2C19, and CYP3A4 in Healthy Volunteers.Clinical pharmacokinetics · 2024Trial
- Towards broader-spectrum direct-acting antivirals against RNA viruses.Nature reviews. Microbiology · 2026Review
- Article
- Nirmatrelvir-Ritonavir-Induced Pancreatitis: A Concern in the COVID Era.ACG case reports journal · 2026Article
- Severe HCoV-OC43 Pneumonia in a 25-Year-Old Woman Following Allogeneic Hematopoietic Stem Cell Transplantation.The clinical respiratory journal · 2026Article
- Enzyme-substrate-inactivator complex formation can impact time-dependent inhibition kinetics.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- Drug Repurposing in Oncology: A Strategic Pathway to Unlocking New Therapeutic Potential.Therapeutic innovation & regulatory science · 2026Review
- Addressing model overcomplexity in drug-drug interaction prediction with molecular fingerprints.Journal of cheminformatics · 2026Article
- Role of metabolites in drug-drug interactions.Drug metabolism and pharmacokinetics · 2026Review
- Review
- Effects of Newer Veterinary Macrolide Antimicrobials on the CYP3A-Dependent Metabolism in Cattle Liver Microsomes: Potential Metabolic Drug-Drug Interaction with Monensin.Animals : an open access journal from MDPI · 2026Article
- InfoMedex: drug-drug interaction prediction via a multimodal CNN-transformer model.Frontiers in drug safety and regulation · 2026Article
- Exploring the roles of cytochrome P450 enzymes and their inhibitors in cancers and non-neoplastic human diseases.Archives of pharmacal research · 2025Review
- Mechanism of intermittent dosing of fluoxetine in premenstrual dysphoric disorder.Archives of women's mental health · 2025Review
- The Effects of Ritonavir on the Pharmacokinetics of Tofacitinib in Rats.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Efficacy and safety of switching from lopinavir/ritonavir-based regimens to bictegravir/emtricitabine/tenofovir alafenamide in people living with HIV: A multicenter retrospective study.Virologica Sinica · 2025Article
- Divergent resistance pathways amongst SARS-CoV-2 PLpro inhibitors highlight the need for scaffold diversity.PLoS pathogens · 2025Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ritonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and is often applied as a booster for drugs with low oral bioavailability due to CYP3A4-mediated biotransformation, as in the treatment of HIV (e.g., lopinavir/ritonavir) and more recently COVID-19 (Paxlovid or nirmatrelvir/ritonavir). Despite its clinical importance, the exact mechanism of ritonavir-mediated CYP3A4 inactivation is still not fully understood. Nonetheless, ritonavir is clearly a potent mechanism-based inactivator, which irreversibly blocks CYP3A4. Here, we discuss four fundamentally different mechanisms proposed for this irreversible inactivation/inhibition, namely the (I) formation of a metabolic-intermediate complex (MIC), tightly coordinating to the heme group; (II) strong ligation of unmodified ritonavir to the heme iron; (III) heme destruction; and (IV) covalent attachment of a reactive ritonavir intermediate to the CYP3A4 apoprotein. Ritonavir further appears to inactivate CYP3A4 and CYP3A5 with similar potency, which is important since ritonavir is applied in patients of all ethnicities. Although it is currently not possible to conclude what the primary mechanism of action in vivo is, it is unlikely that any of the proposed mechanisms are fundamentally wrong. We, therefore, propose that ritonavir markedly inactivates CYP3A through a mixed set of mechanisms. This functional redundancy may well contribute to its overall inhibitory efficacy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.