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Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids
Author(s) -
Morrish Glynn A.,
Foster David J. R.,
Somogyi Andrew A.
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02573.x
Subject(s) - chemistry , methadone , morphine , glucuronide , pharmacology , microsome , in vitro , metabolite , medicine , biochemistry
Aims To 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. Methods M3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µ m ) and the mechanism of inhibition determined for (R)‐ and (S)‐methadone (70–500 µ m ) using three microsomal samples. Results Glucuronide formation displayed single enzyme kinetics. The M3G V max (mean ± SD) was 4.8‐fold greater than M6G V max (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 ). K m values for M3G and M6G formation were not significantly different (1.12 ± 0.37 vs. 1.11 ± 0.31 m m ; P = 0.89, 0.02; − 0.29, 0.32 m m ). 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 K i of 320 ± 42 µ m and 192 ± 12 µ m for M3G and M6G, respectively, and (S)‐methadone K i of 226 ± 30 µ m and 152 ± 20 µ m for M3G and M6G, respectively. K i values for M3G inhibition were significantly greater than for M6G for (R)‐methadone ( P = 0.017, 128; 55, 202 µ m ) and (S)‐methadone ( P = 0.026, 75; 22, 128 µ m ). Conclusions Both 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.