ArticleJournal of clinical pharmacology2022
Physiologically Based Pharmacokinetic Modeling to Assess the Impact of CYP2D6-Mediated Drug-Drug Interactions on Tramadol and O-Desmethyltramadol Exposures via Allosteric and Competitive Inhibition.
Article in Journal of clinical pharmacology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 13 citations in OpenAlex.
- Molecular Mechanisms of Acute Drug Toxicity in Polypharmacy: Analgesic-Psychotropic Interactions.International journal of molecular sciences · 2026Review
- A clinical drug-drug interaction assessment using physiologically based pharmacokinetic modeling: a case study with chloroquine and colchicine.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas · 2026Article
- Pharmacotherapy in kidney disease: what it takes to move from general guidance to specific recommendations to stratified subgroups of patients - the tale of autosomal dominant polycystic kidney disease (ADPKD).Expert opinion on drug metabolism & toxicology · 2025Review
- Enhanced Sensitivity to Tramadol in Diabetic Neuropathic Pain Compared to Nerve Compression Neuropathies: A Population PK/PD Model Analysis.CPT: pharmacometrics & systems pharmacology · 2025Article
- Utilizing Physiologically Based Pharmacokinetic Models to Support Rational Medication in Chinese Elderly Population.Drug design, development and therapy · 2025Article
- Use of CYP2D6 Inhibitors with CYP2D6 Opioids: Association with Emergency Department Visits for Pain.Clinical pharmacology and therapeutics · 2024Article
- Physiologically-based pharmacokinetic modeling of quinidine to establish a CYP3A4, P-gp, and CYP2D6 drug-drug-gene interaction network.CPT: pharmacometrics & systems pharmacology · 2023Article
- Review
- Pharmacogenomics of Cancer Pain Treatment Outcomes in Asian Populations: A Review.Journal of personalized medicine · 2022Review
- Tramadol Versus Codeine in Hand Surgery.Cureus · 2022Article
- Pharmacogenomics and Drug-Induced Phenoconversion Informed Medication Safety Review in the Management of Pain Control and Quality of Life: A Case Report.Journal of personalized medicine · 2022Article
- Considerations for Cannabinoids in Perioperative Care by Anesthesiologists.Journal of clinical medicine · 2022Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tramadol is an opioid medication used to treat moderately severe pain. Cytochrome P450 (CYP) 2D6 inhibition could be important for tramadol, as it decreases the formation of its pharmacologically active metabolite, O-desmethyltramadol, potentially resulting in increased opioid use and misuse. The objective of this study was to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol pharmacokinetics using quinidine and metoprolol as prototypical perpetrator drugs. A physiologically based pharmacokinetic model for tramadol and O-desmethyltramadol was developed and verified in PK-Sim version 8 and linked to respective models of quinidine and metoprolol to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol exposure. Our results show that there is a differentiated impact of CYP2D6 inhibitors on tramadol and O-desmethyltramadol based on their mechanisms of inhibition. Following allosteric inhibition by a single dose of quinidine, the exposure of both tramadol (51% increase) and O-desmethyltramadol (52% decrease) was predicted to be significantly altered after concomitant administration of a single dose of tramadol. Following multiple-dose administration of tramadol and a single-dose or multiple-dose administration of quinidine, the inhibitory effect of quinidine was predicted to be long (≈42 hours) and to alter exposure of tramadol and O-desmethyltramadol by up to 60%, suggesting that coadministration of quinidine and tramadol should be avoided clinically. In comparison, there is no predicted significant impact of metoprolol on tramadol and O-desmethyltramadol exposure. In fact, tramadol is predicted to act as a CYP2D6 perpetrator and increase metoprolol exposure, which may necessitate the need for dose separation.
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Registered trials
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