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Lona L. Christrup - One of the best experts on this subject based on the ideXlab platform.
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The mu1, mu2, delta, kappa opioid receptor binding profiles of Methadone stereoisomers and morphine.
Life sciences, 1995Co-Authors: Kim Kristensen, Christian Broen Christensen, Lona L. ChristrupAbstract:The binding affinities of racemic Methadone and its optical isomers R-Methadone and S-Methadone were evaluated for the opioid receptors mu1, mu2, delta and kappa, in comparison with that of morphine. The analgesic R-Methadone had a 10-fold higher affinity for mu1 receptors than S-Methadone (IC50 3.0 nM and 26.4 nM, respectively). At the mu2 receptor, the IC50 value of R-Methadone was 6.9 nM and 88 nM for S-Methadone, respectively. As expected, R-Methadone had twice the affinity for mu1 and mu2 receptors than the racemate. All of the compounds tested had low affinity for the delta and kappa receptors. This result suggests that S-Methadone does not essentially contribute to opioid effect of racemic Methadone. R-Methadone has a receptor binding profile which resembles that of morphine.
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Pharmacology letterThe mu1, mu2, delta, kappa opioid receptor binding profiles of Methadone stereoisomers and morphine
Life Sciences, 1994Co-Authors: Kim Kristensen, Christian Broen Christensen, Lona L. ChristrupAbstract:The finding affinities of racemic Methadone and its optical isomers R-Methadone and S-Methadone were evaluated for the opioid receptors mu1, mu2, delta and kappa, in comparison with that of morphine. The analgesic R-Methadone had a 10-fold higher affinity for mu1 receptors than S-Methadone (IC50 3.0 nM and 26.4 nM, respectively). At the mu2 receptor, the IC50 value of R-Methadone was 6.9 nM and 88 nM for S-Methadone, respectively. As expected, R-Methadone had twice the affinity for mu1 and mu2 receptors than the racemate. All of the compounds tested had low affinity for the delta and kappa receptors. This results suggests that S-Methadone does not essentially contribute to opioid effect of racemic Methadone. R-Methadone has a receptor binding profile which resembles that of morphine.
Bruno Megarbane - One of the best experts on this subject based on the ideXlab platform.
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Respiratory effects of diazepam/Methadone combination in rats: A study based on concentration/effect relationships.
Drug Alcohol Depend, 2013Co-Authors: Lucie Chevillard, Frédéric Baud, Patricia Risede, Xavier Decleves, Bruno MegarbaneAbstract:BACKGROUND: Methadone may cause respiratory depression and fatalities. Concomitant use of benzodiazepines in Methadone-treated patients for chronic pain or as maintenance therapy for opiate abuse is common. However, the exact contribution of benzodiazepines to Methadone-induced respiratory toxicity remains debatable. METHODS: We investigated the respiratory effects of the combination diazepam (20mg/kg)/Methadone (5mg/kg) in the rat, focusing on Methadone concentration/effect relationships. Respiratory effects were studied using arterial blood gases and whole-body plethysmography. Plasma concentrations of both R- and S-Methadone enantiomers were measured using high-performance liquid chiral chromatography coupled to mass spectrometry. To clarify mechanisms of diazepam/Methadone interaction, Methadone metabolism was investigated in vitro using rat liver microsomes. RESULTS: Diazepam/Methadone co-administration significantly increased Methadone-related effects on inspiratory time (p
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Respiratory effects of diazepam/Methadone combination in rats: A study based on concentration/effect relationships.
Drug Alcohol Depend, 2013Co-Authors: Lucie Chevillard, Frédéric Baud, Patricia Risede, Xavier Decleves, Bruno MegarbaneAbstract:BACKGROUND: Methadone may cause respiratory depression and fatalities. Concomitant use of benzodiazepines in Methadone-treated patients for chronic pain or as maintenance therapy for opiate abuse is common. However, the exact contribution of benzodiazepines to Methadone-induced respiratory toxicity remains debatable. METHODS: We investigated the respiratory effects of the combination diazepam (20mg/kg)/Methadone (5mg/kg) in the rat, focusing on Methadone concentration/effect relationships. Respiratory effects were studied using arterial blood gases and whole-body plethysmography. Plasma concentrations of both R- and S-Methadone enantiomers were measured using high-performance liquid chiral chromatography coupled to mass spectrometry. To clarify mechanisms of diazepam/Methadone interaction, Methadone metabolism was investigated in vitro using rat liver microsomes. RESULTS: Diazepam/Methadone co-administration significantly increased Methadone-related effects on inspiratory time (p
Evan D. Kharasch - One of the best experts on this subject based on the ideXlab platform.
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Cytochrome P4503A does not mediate the interaction between Methadone and ritonavir-lopinavir.
Drug metabolism and disposition: the biological fate of chemicals, 2013Co-Authors: Evan D. Kharasch, Kristi StubbertAbstract:Plasma concentrations of orally administered Methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavir-lopinavir on intravenous and oral Methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of Methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma Methadone enantiomer concentrations in half, with an average 2.6- and 1.5-fold induction of systemic and apparent oral Methadone clearances. Induction was attributable to stereoselectively increased hepatic Methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between Methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil’s systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between Methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced Methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on Methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose Methadone disposition.
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mechanism of ritonavir changes in Methadone pharmacokinetics and pharmacodynamics i evidence against cyp3a mediation of Methadone clearance
Clinical Pharmacology & Therapeutics, 2008Co-Authors: Evan D. Kharasch, Dale Whittington, Pamela Sheffels Bedynek, Sang Park, Alysa Walker, Christine HofferAbstract:Methadone is a cornerstone therapy of opiate dependence.1 Methadone maintenance prevents withdrawal, craving, concomitant use of opiates and illicit drugs, and is a vital public health strategy for HIV/AIDS risk reduction. Methadone is an efficacious and cost-effective first- or second-line treatment for acute, chronic, neuropathic, and cancer pain, in adults and children, and can be administered via multiple routes.2,3 Methadone use increased more than 700% between 1997-2004.4 Attainment and maintenance of predictable and reproducible Methadone concentrations within therapeutic ranges is confounded, however, by considerable and unpredictable interindividual variability in Methadone pharmacokinetics, susceptibility to drug interactions, and a long elimination half-life.5,6 Potential consequences include inadequate treatment or adverse events such as withdrawal, respiratory depression, or death. Methadone-related adverse events increased nearly 1800% between 1997-2004, and it is the sixth most frequent suspected drug in death and serious nonfatal outcomes.4 Methadone is mainly cleared by hepatic metabolism, and also by urinary excretion of unchanged drug. The primary metabolic route is N-demethylation to pharmacologically inactive 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). There is large interindividual variability in Methadone clearance.5,7 Methadone drug interactions occur with numerous CYP inducers and inhibitors.5,6 For over a decade, Methadone clearance has been attributed to CYP3A4. Numerous in vitro studies demonstrated CYP3A4 involvement in Methadone N-demethylation by human liver or intestinal microsomes and expressed CYPs.8-12 Methadone metabolism and clearance in vivo have been widely attributed to CYP3A4; numerous dosing guidelines warn about potential CYP3A4-mediated Methadone drug interactions and the need to adjust dosing accordingly.5-7,10,13-16 Methadone is a substrate for the efflux transporter P-glycoprotein (P-gp) in vitro and in brain in animals in vivo, which influences Methadone brain access, pharmacodynamics, and analgesia.17-19 The role of P-gp in Methadone brain penetration, pharmacodynamics and clinical effects, is unknown. The epidemics of opioid dependence and HIV/AIDS are inextricably intertwined and Methadone-HIV/AIDS cotreatment increasingly common. Antiretrovirals are notorious perpetrators of drug interactions. The protease inhibitors ritonavir, indinavir, nelfinavir, saquinavir, lopinavir, and amprenavir can induce and/or inhibit the metabolism and clearance of numerous drugs in vivo.6 Ritonavir is the most potent and efficacious inhibitor of CYP3A isoforms. Duration of ritonavir administration may affect the degree of CYP3A inhibition, with short-term dosing causing inhibition, with longer administration causing apparent induction with concurrent inhibition.20,21 Ritonavir, both alone and in combination with other antiretrovirals, causes decreases in both S- and R-Methadone (active enantiomer) plasma concentrations and area under the concentration-time curve, and variably causes Methadone withdrawal.6 Ritonavir effects on Methadone clearance have been attributed to CYP3A4. Nonetheless, the apparent paradox of ritonavir induction of Methadone clearance, despite profound inhibition of CYP3A4 activity, has never been addressed. Indeed, mechanism(s) of ritonavir modulation of Methadone pharmacokinetics and clinical effects still remain fundamentally unknown. Typically, Methadone-ritonavir interaction studies have evaluated Methadone but not EDDP plasma concentrations, and only some have evaluated stereoselectivity. Thus effects on Methadone metabolism, and their stereoselectivity, are unknown. The purpose of this clinical investigation was to determine: 1) mechanism(s) of acute and steady-state ritonavir alterations in Methadone disposition and clinical effect; including the role of CYP3A4/5- and/or P-gp-mediated Methadone bioavailability, first-pass metabolism, and systemic clearance; 2) the influence of ritonavir on Methadone pharmacodynamics, 3) acute and steady-state ritonavir effects on hepatic CYP3A4/5, first-pass CYP3A4/5, and intestinal P-gp activities using validated in vivo probes; 4) the ability of a noninvasive in vivo CYP3A4/5 probe to detect ritonavir drug interactions. A comprehensive crossover investigation was conducted in healthy volunteers (Figure 1). An accompanying manuscript describes ritonavir effects on hepatic and intestinal CYP3A4/5 and P-gp activities.22 This manuscript reports ritonavir effects on Methadone pharmacokinetics and pharmacodynamics. Intravenous and oral (deuterium-labeled) Methadone were simultaneously administered to concurrently assess drug kinetics, hepatic extraction and bioavailability, and, by avoiding a crossover design (for different routes of administration on different days) thereby diminish interday variability and double the protocol efficiency.12 Miosis was used to assess one of the Methadone clinical effects and pharmacodynamics. Figure 1 Study protocol for ritonavir-Methadone interaction. Shaded boxes show drug administration and/or blood and urine sampling.
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role of cyp2b6 in stereoselective human Methadone metabolism
Anesthesiology, 2008Co-Authors: Rheem A. Totah, Pamela Sheffels, Toni Roberts, Kenneth E. Thummel, Dale Whittington, Evan D. KharaschAbstract:Background: Metabolism and clearance of racemic Methadone are stereoselective and highly variable, yet the mechanism remains largely unknown. Initial in vitro studies attributed Methadone metabolism to cytochrome P4503A4 (CYP3A4). CYP3A4 was also assumed responsible for Methadone clearance in vivo. Nevertheless, recent clinical data do not support a primary role for CYP3A4 and suggest that CYP2B6 may mediate Methadone clearance. Expressed CYP2B6 and also CYP2C19 N-demethylate Methadone in vitro. This investigation tested the hypothesis that CYPs 2B6, 3A4, and/or 2C19 are responsible for stereoselective Methadone metabolism in human liver microsomes and in vivo. Methods: N-demethylation of racemic Methadone and individual enantiomers by expressed CYPs 2B6, 2C19, and 3A4 was evaluated. Stereoselective microsomal Methadone metabolism was quantified, compared with CYP 2B6 and 3A4 content, and probed using CYP isoform-selective inhibitors. A crossover clinical investigation (control, CYP2B6 and CYP3A4 induction by rifampin, CYP3A inhibition by troleandomycin and grapefruit juice) evaluated stereoselective Methadone disposition. Results: At clinical concentrations, Methadone enantiomer N-demethylation by recombinant CYPs 2B6, 3A4, and 2C19 was S > R, S = R, and S R) occurred in livers expressing high levels of CYP2B6 compared with CYP3A4. Clopidogrel, troleandomycin, and (+)-N-3-benzyl-nirvanol, selective inhibitors of CYPs 2B6, 3A4, and 2C19, respectively, inhibited microsomal Methadone metabolism by 50-60%, 20-30%, and less than 10%. Only Inhibition by clopidogrel was stereoselective. Clinically, rifampin diminished both R- and S-Methadone plasma concentrations, but troleandomycin and grapefruit juice altered neither R- nor S-Methadone concentrations. Plasma R/S-Methadone ratios were increased by rifampin but unchanged by CYP3A Inhibition. Conclusions: These results suggest a significant role for CYP2B6, but not CYP3A, in stereoselective human Methadone metabolism and disposition.
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role of hepatic and intestinal cytochrome p450 3a and 2b6 in the metabolism disposition and miotic effects of Methadone
Clinical Pharmacology & Therapeutics, 2004Co-Authors: Evan D. Kharasch, Christine Hoffer, Dale Whittington, Pamela SheffelsAbstract:Background The disposition of the long-acting opioid Methadone, used to prevent opiate withdrawal and treat short- and long-lasting pain, is highly variable. Methadone undergoes N-demethylation to the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP), catalyzed in vitro by intestinal, hepatic, and expressed cytochrome P450 (CYP) 3A4. However, the role of CYP3A4 in human Methadone disposition in vivo is unclear. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) Methadone metabolism and clearance in humans. Methods Healthy volunteers were studied in a randomized, balanced, 4-way crossover study. They received intravenous (IV) midazolam (to assess CYP3A4 activity) and then simultaneous oral deuterium-labeled and IV unlabeled Methadone after pretreatment with rifampin (INN, rifampicin) (hepatic/intestinal CYP3A induction), troleandomycin (hepatic/intestinal CYP3A inhibition), grapefruit juice (selective intestinal CYP3A inhibition), or nothing. Methadone effects were measured by dark-adapted pupil diameter. CYP isoforms catalyzing Methadone metabolism by human liver microsomes and expressed CYPs in vitro were also evaluated. Results Methadone had high oral bioavailability (70%) and low intestinal (22%) and hepatic (9%) extraction, and there was a significant correlation (r = 0.94, P < .001) between oral bioavailability and intestinal (but not hepatic) availability. Rifampin decreased bioavailability and oral and IV Methadone plasma concentrations and increased IV clearance (4.42 ± 1.00 mL · kg−1 · min−1 versus 1.61 ± 0.67 mL · kg−1 · min−1, P < .05) and oral clearance (8.50 ± 3.68 mL · kg−1 · min−1 versus 2.05 ± 0.92 mL · kg−1 · min−1, P < .05), EDDP/Methadone area under the curve (AUC) ratios, EDDP formation clearances, and hepatic extraction (0.27 ± 0.06 versus 0.09 ± 0.04, P < .05). Troleandomycin and grapefruit juice decreased the EDDP/Methadone AUC ratio after oral Methadone (0.17 ± 0.10 and 0.14 ± 0.06 versus 0.27 ± 0.20, P < .05) but not IV Methadone and had no effect on Methadone plasma concentrations, IV clearance (1.29 ± 0.41 mL · kg−1 · min−1 and 1.48 ± 0.55 mL · kg−1 · min−1) or oral clearance (2.05 ± 1.52 mL · kg−1 · min−1 and 1.89 ± 1.07 mL · kg−1 · min−1), or other kinetic parameters. There was no correlation between Methadone clearance and hepatic CYP3A4 activity. Pupil diameter changes reflected plasma Methadone concentrations. In vitro experiments showed a predominant role for both CYP3A4 and CYP2B6 in liver microsomal Methadone N-demethylation. Conclusion First-pass intestinal metabolism is a determinant of Methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human Methadone N-demethylation but has no significant effect on Methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on Methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter Methadone disposition. Clinical Pharmacology & Therapeutics (2004) 76, 250–269; doi: 10.1016/j.clpt.2004.05.003
Norman Smalldridge - One of the best experts on this subject based on the ideXlab platform.
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Safe storage of Methadone in the home - An audit of the effectiveness of safety information giving
Harm Reduction Journal, 2005Co-Authors: Roger N. Bloor, Rosanna Mcauley, Norman SmalldridgeAbstract:Background: Accidental poisoning by Methadone occurs, particularly as a result of children ingesting a parent's Methadone. Health care professionals have a responsibility to provide information and guidance to Methadone users on safe storage of Methadone. The objective of the study was to audit the effectiveness of information giving on the safety of Methadone consumption, dose measurement and storage, and the effectiveness of sources of advice available for patients. Methods: The study was undertaken prior to the introduction of a scheme for the supervised consumption of Methadone, in the setting of an NHS Methadone clinic serving a district population of 490,000 in the UK. 185 consecutive patients attending a Methadone clinic to collect a Methadone prescription were the subject of an anonymous survey. Issues of safety of Methadone consumption, storage and safety information provisions were assessed. A telephone survey of the community pharmacists dispensing the Methadone covered the availability of measuring devices and provision of advice on safety was undertaken. Results: Methadone was stored in a variety of locations, a cupboard being most frequent. 95 patients (60.1%) had children either living in or visiting their home. All stored their Methadone in a bottle with a child resistant lid; the majority measured doses using either the container supplied by the pharmacist or a plastic measure. 126 patients (78%) confirmed that a pharmacist provided a measuring container on their first visit, 24 (15%) were given a measure on every visit to the pharmacist. Advice on safe storage was recalled by 30% of the patients, and advice on measuring Methadone by 28%. Methadone was seen as potentially dangerous by 82% of the patients. Conclusion: The risks resulting from unsafe storage of Methadone may be reduced by daily instalment prescribing and provision of measuring containers on request. Recall of provision of information on safety issues is poor and the adoption of a standard policy on provision information should be seen as a priority. A re-audit of safety of storage of Methadone is recommended following the introduction of a standard policy on information provision.
Roger N. Bloor - One of the best experts on this subject based on the ideXlab platform.
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Awareness of the need for safe storage of Methadone at home is not improved by the use of protocols on recording information giving
Harm Reduction Journal, 2008Co-Authors: Annemarie Mullin, Rosanna J Mcauley, Derrett J Watts, Ilana B Crome, Roger N. BloorAbstract:Background Methadone is a synthetic, narcotic analgesic used in the treatment of drug misuse. Tragedies involving children being poisoned by the accidental ingestion of Methadone are no longer a rare occurrence. Following an audit of the effectiveness of the provision and recall of information to patients attending an NHS Methadone Clinic a protocol was introduced to ensure that staff documented the provision of such information and patients gave a written confirmation that they had received the information. Methods The study was undertaken in the setting of an NHS Methadone clinic with the aim of re- auditing the storage of Methadone at home following the introduction of the new protocols. 174 patients completed an anonymous questionnaire regarding where they store Methadone at home and whether they recall being given advice about safe storage. Community pharmacists were contacted by telephone to assess the level of advice given to Methadone patients regarding safety. Results Only 49 (28.2%) patients recalled being given advice about safe storage, 24 (13.8%) recalled that information was provided by clinic staff. 170 (97.7%) patients regard Methadone as being dangerous. (28.2%). Methadone is most commonly stored in a cupboard (37.9%). All Methadone is dispensed in a bottle with a child resistant cap on it. All patients reported they stored their Methadone in the original bottle provided by the pharmacist. Conclusion Recall of information on safety issues is very poor. Provision of written as well as verbal information is needed. The use of printed safety information cards which patients can take away for future reference may be of use. It is the responsibility of health professionals to ensure they provide information and advice to Methadone users on the safe storage of their Methadone at home.
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Safe storage of Methadone in the home - An audit of the effectiveness of safety information giving
Harm Reduction Journal, 2005Co-Authors: Roger N. Bloor, Rosanna Mcauley, Norman SmalldridgeAbstract:Background: Accidental poisoning by Methadone occurs, particularly as a result of children ingesting a parent's Methadone. Health care professionals have a responsibility to provide information and guidance to Methadone users on safe storage of Methadone. The objective of the study was to audit the effectiveness of information giving on the safety of Methadone consumption, dose measurement and storage, and the effectiveness of sources of advice available for patients. Methods: The study was undertaken prior to the introduction of a scheme for the supervised consumption of Methadone, in the setting of an NHS Methadone clinic serving a district population of 490,000 in the UK. 185 consecutive patients attending a Methadone clinic to collect a Methadone prescription were the subject of an anonymous survey. Issues of safety of Methadone consumption, storage and safety information provisions were assessed. A telephone survey of the community pharmacists dispensing the Methadone covered the availability of measuring devices and provision of advice on safety was undertaken. Results: Methadone was stored in a variety of locations, a cupboard being most frequent. 95 patients (60.1%) had children either living in or visiting their home. All stored their Methadone in a bottle with a child resistant lid; the majority measured doses using either the container supplied by the pharmacist or a plastic measure. 126 patients (78%) confirmed that a pharmacist provided a measuring container on their first visit, 24 (15%) were given a measure on every visit to the pharmacist. Advice on safe storage was recalled by 30% of the patients, and advice on measuring Methadone by 28%. Methadone was seen as potentially dangerous by 82% of the patients. Conclusion: The risks resulting from unsafe storage of Methadone may be reduced by daily instalment prescribing and provision of measuring containers on request. Recall of provision of information on safety issues is poor and the adoption of a standard policy on provision information should be seen as a priority. A re-audit of safety of storage of Methadone is recommended following the introduction of a standard policy on information provision.
