ArticleBritish journal of clinical pharmacology2006
Differential in vitro inhibition of M3G and M6G formation from morphine by (R)- and (S)-methadone and structurally related opioids.
Article in British journal of clinical pharmacology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 18 citations in OpenAlex.
- Interactions between long-acting antiretrovirals and opioids: a call for clinical awareness.Clinical microbiology reviews · 2026Review
- Hydrocodone, Oxycodone, and Morphine Metabolism and Drug-Drug Interactions.The Journal of pharmacology and experimental therapeutics · 2023Review
- Physiologically-Based Pharmacokinetic Model of Morphine and Morphine-3-Glucuronide in Nonalcoholic Steatohepatitis.Clinical pharmacology and therapeutics · 2021Article
- Computational framework for predictive PBPK-PD-Tox simulations of opioids and antidotes.Journal of pharmacokinetics and pharmacodynamics · 2019Article
- Could Postnatal Age-Related Uridine Diphosphate Glucuronic Acid Be a Rate-Limiting Factor in the Metabolism of Morphine During the First Week of Life?CPT: pharmacometrics & systems pharmacology · 2019Article
- Pharmacogenetics of Methadone Response.Molecular diagnosis & therapy · 2018Review
- Prediction of morphine clearance in the paediatric population : how accurate are the available pharmacokinetic models?Clinical pharmacokinetics · 2012Review
- From Pediatric Covariate Model to Semiphysiological Function for Maturation: Part II-Sensitivity to Physiological and Physicochemical Properties.CPT: pharmacometrics & systems pharmacology · 2012Article
- Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects.British journal of clinical pharmacology · 2012Article
- Endogenous opiates and behavior: 2006.Peptides · 2007Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsTo determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids.
methodsM3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 microm) and the mechanism of inhibition determined for (R)- and (S)-methadone (70-500 microm) using three microsomal samples.
resultsGlucuronide formation displayed single enzyme kinetics. The M3G Vmax (mean+/-SD) was 4.8-fold greater than M6G Vmax (555+/-110 vs. 115+/-19 nmol mg-1 protein h-1; P=0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg-1 protein h-1). Km values for M3G and M6G formation were not significantly different (1.12+/-0.37 vs. 1.11+/-0.31 mm; P=0.89, 0.02; -0.29, 0.32 mm). M3G and M6G formation was inhibited (P<0.01) with a significant increase in the M3G/M6G ratio (P<0.01) for all compounds tested. Detailed analysis with (R)- and (S)-methadone revealed noncompetitive inhibition with (R)-methadone Ki of 320+/-42 microm and 192+/-12 microm for M3G and M6G, respectively, and (S)-methadone Ki of 226+/-30 microm and 152+/-20 microm for M3G and M6G, respectively. Ki values for M3G inhibition were significantly greater than for M6G for (R)-methadone (P=0.017, 128; 55, 202 microm) and (S)-methadone (P=0.026, 75; 22, 128 microm).
conclusionsBoth methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadone-maintained patients and reduced relative formation of the opioid active M6G compared with M3G.
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