Morphine-3-Glucuronide — A potent antagonist of morphine analgesia

Smith, M. T.; Cramond, Tess

doi:10.1016/0304-3959(90)92509-o

Cited by 79 publications

(107 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…M3G has also .The dialysate was been shown to be a potent antagonist of morphine-induced morphine by use of analgesia in rats (Smith et al, 1990 (Gong et al, 1991). Although M3G has been demonstrated to be antagonistic to morphine-or M6G-induced analgesic and ventilatory effect in the rat (Gong et al, 1992), the exact mechanisms of action remain obscure.…”

Section: Discussionmentioning

confidence: 99%

“…It antagonizes the analgesic (Smith et al, 1990) and ventilatory (Gong et al, 1991;1992) effects of morphine as well as of M6G, and appears to have long biological half-life (Ekblom et al, 1993). Because of these observations, it has been suggested that the ratio M6G/M3G in serum and/or CSF may be important in the overall analgesic activity of morphine (Bowsher, 1993).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Barjavel

Scherrmann

Bhargava

1995

British J Pharmacology

View full text Add to dashboard Cite

1 The effect of morphine (10 mg kg-', s.c.) on the analgesic response measured by the tail-flick method was determined in male Sprague-Dawley rats. The analgesic response to morphine was correlated with the levels of morphine and its metabolites collected by microdialysis from the cortical extracellular fluid (ECF).2 The analgesic response to morphine lasted for 4 h. The concentration of morphine during a 4 h collection period was significantly higher than the metabolites concentration. The relative concentration of morphine and its metabolites during the 4 h period was 70 and 30% respectively. 3 The analgesic response during the first 2.25 h period accounted for more than 82% of the total analgesia as determined by the area under the time-response curve (AUC). The concentration of morphine and its metabolites during the same period were 78 and 22%, respectively, but they did not differ during the 2.25-4.0 h period (52 and 48%). 4 The half-life for morphine and its metabolites were similar, the maximal achievable concentration Cma, and AUCO4 h were lower for metabolites but the time to reach maximum concentration was higher for morphine metabolites than for morphine. The ratio of the concentration of metabolites to the concentration of morphine in the cortical ECF increased with time whereas the analgesic response to morphine decreased with time. 5 At several time points following morphine injection even though the levels of morphine were the same, the concentration of metabolites (mainly M3G) differed and thus the ratio [metabolite/morphine]. A plot of [metabolite]/[morphine] vs. analgesia gave a high correlation coefficient. Since M3G has been shown to be antianalgesic and is the only metabolite of morphine in the rat, it is concluded that the levels of this metabolite may regulate the analgesic effect of morphine in the rat.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Barjavel

Scherrmann

Bhargava

1995

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…However, M6G is a more potent µ opioid agonist [1] and a number of studies have shown its contribution to analgesia, particularly after a high dose or during chronic morphine therapy [2,3,51,52]. In contrast, several animal studies have shown that M3G attenuates the opioid effects of morphine [5,6,53,54], although this has yet to be well demonstrated in humans. Thus, decreased M6G formation combined with an increase in the M3G/M6G ratio may result in decreased analgesia and an increase in excitatory effects.…”

Section: Tablementioning

confidence: 99%

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

Morrish

Foster

Somogyi

2005

Brit J Clinical Pharma

View full text Add to dashboard Cite

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)-and (S)-methadone and structurally related opioids Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia 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 µ M ) and the mechanism of inhibition determined for (R)-and (S)-methadone (70-500 µ M ) using three microsomal samples. ResultsGlucuronide 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 ). 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 methadonemaintained patients and reduced relative formation of the opioid active M6G compared with M3G. IntroductionMorphine is the gold standard opioid for the treatment of moderate to severe acute and chronic pain. Morphine is primarily cleared via glucuronidation to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M6G is a potent µ -opioid agonist [1] with clinical studies suggesting it contributes to analgesia after the administration of morphine [2,3]. M3G has no anal- [11,12,14]. Investigations with expressed recombinant human UDPglucuronosyltransferase (UGT) enzymes have shown UGT1A1, 1A3, 1A6, 1A8, 1A9, 1A10 and 2B7 all metabolize morphine to M3G [15][16][17]. However, only UGT2B7 has been shown to form M6G [17,18]. The relative contribution of these isoforms to the overall glucuronidation of morphine is still unknown. Only one investigation using human liver microsomes has shown the possible involvement of more than one UGT isoform in M3G formation, with the suggested involvement of a high-affinity, low-capacity enzyme (with a mean K m and V max of 5.3 µ M and 18 nmol mg − 1 protein h...

show abstract

“…In turn, morphine may also mediate its effects through formation of active metabolites including the 6-glucuronide [5][6][7]. In addition morphine-3-glucuronide binds to opiate receptors with a low affinity [8,9], and may be a functional antagonist of several of the effects of morphine [10,11]. Thus, the overall effect of morphine and thereby also at least some effects of ethylmorphine, could depend upon the ex- Because ethylmorphine is abused in large doses for its euphoric potential the dose given in this study was high.…”

Section: Introductionmentioning

confidence: 99%

Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.

Aasmundstad¹,

Xu²,

Johansson³

et al. 1995

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture Cosylan® were investigated in 10 healthy subjects. 2 The median urinary recovery of ethylmorphine and measured metabolites was 77% over 48 h. The median tmax of unchanged ethylmorphine was 45 min, and the terminal elimination t'/2 was 2 h. Ethylmorphine-6-glucuronide was found to be the major metabolite. 3 Two subjects had significantly lower urinary recovery (0,48 h) of morphine and morphine-glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MRO) and partial metabolic clearances (CLmo) for O-deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine type. 4 Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five homozygote (wt/wt) and five heterozygote subjects. Two subjects phenotypically classified as poor metabolisers were genotypically CYP2D6A/wt and CYP2D6D/wt, respectively. 5 Serum and urine samples taken more than 8 and 24 h after administration of ethylmorphine respectively, contained morphine and morphine-glucuronides, but no ethylmorphine, ethylmorphine-6-glucuronide or (serum only) norethylmorphine. Norethylmorphine could be detected after hydrolysis of urine samples in all subjects. The urinary recovery of the active metabolites morphine and morphine-6-glucuronide after administration of ethylmorphine varied by a factor of 9 between individuals. 6 The wide variation in recovery of morphine and morphine-glucuronides after oral administration of ethylmorphine could not be explained simply by a difference in CYP2D6 genotype. Constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administration of ethylmorphine. Norethylmorphine should be included in urine assays for opiates in forensic toxicology, and no firm conclusions about the source of morphine are possible based on serum samples obtained more than 24 h after drug administration.

show abstract

Morphine-3-Glucuronide — A potent antagonist of morphine analgesia

Cited by 79 publications

References 0 publications

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.

Contact Info

Product

Resources

About