Trial reportClinical pharmacology and therapeutics2008
Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance.
Trial report in Clinical pharmacology and therapeutics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
39 citing papers in PubMed, 77 citations in OpenAlex.
- Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease.Pediatric blood & cancer · 2016Trial
- Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism.Anesthesiology · 2015Trial
- Pharmacokinetic interaction between telaprevir and methadone.Antimicrobial agents and chemotherapy · 2013Trial
- Concurrent assessment of hepatic and intestinal cytochrome P450 3A activities using deuterated alfentanil.Clinical pharmacology and therapeutics · 2011Trial
- Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activities.Clinical pharmacology and therapeutics · 2008Trial
- Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment.Drugs in R&D · 2024Article
- Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism.Drugs in R&D · 2024Article
- Methadone pharmacogenetics in vitro and in vivo: Metabolism by CYP2B6 polymorphic variants and genetic variability in paediatric disposition.British journal of clinical pharmacology · 2022Article
- Quantitative Prediction of Drug Interactions Caused by Cytochrome P450 2B6 Inhibition or Induction.Clinical pharmacokinetics · 2022Article
- Brain/blood ratios of methadone and ABCB1 polymorphisms in methadone-related deaths.International journal of legal medicine · 2021Article
- Pharmacogenomics of methadone: a narrative review of the literature.Pharmacogenomics · 2020Review
- Drug-Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir.Clinical pharmacokinetics · 2018Review
- Current Concepts in Methadone Metabolism and Transport.Clinical pharmacology in drug development · 2017Article
- Continuous-Flow Synthesis of Deuterium-Labeled Antidiabetic Chalcones: Studies towards the Selective Deuteration of the Alkynone Core.Molecules (Basel, Switzerland) · 2016Article
- Drug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir.Clinical pharmacokinetics · 2016Review
- Differences in Methadone Metabolism by CYP2B6 Variants.Drug metabolism and disposition: the biological fate of chemicals · 2015Article
- Cyclosporine-inhibitable cerebral drug transport does not influence clinical methadone pharmacodynamics.Anesthesiology · 2014Article
- Automated radiochemical synthesis and biodistribution of [¹¹C]l-α-acetylmethadol ([¹¹C]LAAM).Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine · 2014Article
- Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo.Biochemical pharmacology · 2014Article
- Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined ritonavir effects on stereoselective methadone pharmacokinetics and clinical effects (pupillary miosis) in healthy human immunodeficiency virus-negative volunteers. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone after no ritonavir, short-term (3-day) ritonavir, and steady-state ritonavir. Acute and steady-state ritonavir, respectively, caused 1.5- and 2-fold induction of systemic and apparent oral R- and S-methadone clearances. Ritonavir increased renal clearance 40-50%, and stereoselectively (S > R) increased hepatic methadone N-demethylation 50-80%, extraction twofold, and clearance twofold. Bioavailability was unchanged despite significant inhibition of intestinal P-glycoprotein. Intestinal and hepatic CYP3A was inhibited > 70%. Ritonavir shifted methadone plasma concentration-miosis curves leftward and upward. Rapid ritonavir induction of methadone clearance results from increased renal clearance and induced hepatic metabolism. Induction of methadone metabolism occurred despite profound CYP3A inhibition, suggesting no role for CYP3A in clinical methadone metabolism and clearance. Ritonavir may alter methadone pharmacodynamics.
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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 OpenQuestion graph.