Randomized placebo-controlled trial of the activity of the morphine glucuronides

Penson, Richard T.; Joel, Simon P.; Bakhshi, K.N.; Clark, Simon J.; Langford, R. M.; Slevin, M. L.

doi:10.1067/mcp.2000.111934

Cited by 112 publications

(81 citation statements)

References 30 publications

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“…Further investigation on the contribution of renal transporters to morphine CL would improve the current PBPK model. On another note, the current morphine PBPK model can predict the morphine concentration‐time profile, but not the metabolite profiles for morphine‐3‐glucuronide (an inactive metabolite) and morphine‐6‐glucuronide (an active metabolite) 41. In order to capture the exposure levels of morphine metabolites, we need to develop the combined PBPK models of morphine and its metabolites, which will be considered in a next study.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

Emoto

Fukuda

Johnson

et al. 2016

CPT Pharmacom & Syst Pharma

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Morphine shows large interindividual variability in its pharmacokinetics; however, the cause of this has not been fully addressed. The variability in morphine disposition is considered to be due to a combination of pharmacogenetic and physiological determinants related to morphine disposition. We previously reported the effect of organic cation transporter (OCT1) genotype on morphine disposition in pediatric patients. To further explore the underlying mechanisms for variability arising from relevant determinants, including OCT1, a physiologically based pharmacokinetic (PBPK) model of morphine was developed. The PBPK model predicted morphine concentration‐time profiles well, in both adults and children. Almost all of the observed morphine clearances in pediatric patients fell within a twofold range of median predicted values for each OCT1 genotype in each age group. This PBPK modeling approach quantitatively demonstrates that OCT1 genotype, age‐related growth, and changes in blood flow as important contributors to morphine pharmacokinetic (PK) variability.

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Section: Discussionmentioning

confidence: 99%

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

Emoto

Fukuda

Johnson

et al. 2016

CPT Pharmacom & Syst Pharma

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“…Preliminary assessment of the toxicity and pharmacokinetics of i.v. M3G reported no excitatory effects [8]; however, investigation of M3G combined with morphine or M6G by this group reported M3G may have been associated with mild symptoms that reflected neuroexcitation in several of the subjects, a finding not observed when morphine or M6G were administered alone [9].…”

Section: Introductionmentioning

confidence: 86%

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

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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...

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“…M3G is an inactive metabolite [17][18], the activity of M6G on µ-opioid receptors has been demonstrated in a number of studies [19][20][21], and this molecule is under investigation as therapeutic agent for the treatment of post-operative pain [22][23][24][25]. From LC/MS-MS results, the concentration ratio M3G/M6G was evaluated ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…In the last years, however, increasing interest has grown towards the role of these metabolites in mediating heroin or morphine action [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. This paper describes a SPE extraction procedure and a validated LC/MS-MS method for the simultaneous determination of heroin metabolites in post-mortem blood samples.…”

Section: M6gmentioning

confidence: 99%

Study of the Ratio between Morphine-3-β-D-Glucuronide and Morphine-6-β-DGlucuronide in Blood Samples from Heroin Fatalities

Froldi¹,

Guerrini²,

Argo³

et al. 2015

J Anal Bioanal Tech

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In heroin fatalities the diagnosis of the cause of death, based only on chemical and toxicological data, may be particularly difficult; a complete knowledge of the case history is fundamental. Thus, for each case analytical results should be interpreted taking into account also autopsy findings, information from the scene and relevant medical history. In fact wide variability is present in post-mortem blood concentration of morphine (MOR), the main metabolite of heroin, which is usually the most important analytical result for the interpretation of the cause of death. Recently, increasing interest has grown towards the role of the metabolites morphine-3-β-D-glucuronide (M3G) and morphine-6-β-D-glucuronide (M6G) in mediating heroin effects. To this purpose SPE technique was employed to extract MOR, M3G and M6G from autopsy blood samples. Subsequently a LC/MS-MS method for the determination of these analytes was developed, using a gradient elution with a binary mobile phase, the analytes being revealed by means of an ESI-QqQ Mass Spectrometer operating in positive ionization and MRM mode. After validation, the method was applied to twenty-one blood specimens collected from cases of suspected acute narcotism which previously underwent a Systematic Toxicological Analysis (STA) to highlight the presence of ethanol and of the main drugs of abuse and/or their metabolites. The concentration ratios of MOR, M3G and M6G were investigated. The influence of some risk factors, such as the contemporary use of alcohol, methadone or cocaine, was also studied. Some important indications emerged: the ratio M3G/M6G, being quite constant, should be a valid reference value to assess toxicity. Furthermore the value of M3G/M6G ratio detected in heroin addict, in this study, is lower than that found in people who assume morphine for therapeutic purposes. This ratio could be of help to overcome the difficult interpretation of chemical and toxicological data.

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Randomized placebo-controlled trial of the activity of the morphine glucuronides

Abstract: M3G appears to be devoid of significant activity; in these circumstances and at these doses, it does not antagonize either the analgesic or respiratory depressant effects of M6G or morphine.

Cited by 112 publications

References 30 publications

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

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

Study of the Ratio between Morphine-3-β-D-Glucuronide and Morphine-6-β-DGlucuronide in Blood Samples from Heroin Fatalities

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