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John O Miners - One of the best experts on this subject based on the ideXlab platform.
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in vitro in vivo extrapolation predicts drug drug interactions arising from inhibition of codeine glucuronidation by Dextropropoxyphene fluconazole ketoconazole and methadone in humans
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Pritsana Raungrut, Verawan Uchaipichat, Benjamas Janchawee, Andrew A. Somogyi, David J. Elliot, John O MinersAbstract:Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro–in vivo extrapolation approaches were used to identify potential drug–drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant ( K m ) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S 50 values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean K m observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for Dextropropoxyphene (3.5 μM), fluconazole (202 μM), ketoconazole (0.66 μM), and methadone (0.32 μM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration–time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by Dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.
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In Vitro–In Vivo Extrapolation Predicts Drug–Drug Interactions Arising from Inhibition of Codeine Glucuronidation by Dextropropoxyphene, Fluconazole, Ketoconazole, and Methadone in Humans
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Pritsana Raungrut, Verawan Uchaipichat, Benjamas Janchawee, Andrew A. Somogyi, David J. Elliot, John O MinersAbstract:Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro–in vivo extrapolation approaches were used to identify potential drug–drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant ( K m ) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S 50 values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean K m observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for Dextropropoxyphene (3.5 μM), fluconazole (202 μM), ketoconazole (0.66 μM), and methadone (0.32 μM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration–time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by Dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.
Jeanlouis Montastruc - One of the best experts on this subject based on the ideXlab platform.
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reporting rate of adverse drug reactions to the french pharmacovigilance system with three step 2 analgesic drugs Dextropropoxyphene tramadol and codeine in combination with paracetamol
British Journal of Clinical Pharmacology, 2009Co-Authors: Neda Tavassoli, Maryse Lapeyremestre, Agnes Sommet, Jeanlouis MontastrucAbstract:AIMS Three ‘weak’ opioid analgesics in association with paracetamol are marketed in France as step 2 analgesics: Dextropropoxyphene, tramadol and codeine. These combinations are involved in several adverse drug reactions (ADRs), but no data are available about their comparative reporting rate. The aim was to compare the reporting rate of ADRs between tramadol/paracetamol (TRM+P), codeine/paracetamol (COD+P) and Dextropropoxyphene/paracetamol (DXP+P).
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Dextropropoxyphene withdrawal from a french university hospital impact on analgesic drug consumption
Fundamental & Clinical Pharmacology, 2009Co-Authors: Sabine Gaubert, Christine Damasemichel, Atul Pathak, Jeanlouis MontastrucAbstract:Dextropropoxyphene is a weak opioid analgesic, widely used as a step 2 analgesic (according to WHO classification) in combination with peripheral analgesics, mainly paracetamol. Recent data have underlined its poor analgesic efficacy (in comparison with paracetamol), risks of serious adverse drug reactions (i.e. hepatic reactions, hallucinations, abuse, withdrawal symptoms, hypoglycaemia), possible lethality after overdose, its risk of accumulation in patients with renal failure or in elderly people and some pharmacokinetic insufficiencies (i.e. different half-lives for Dextropropoxyphene and paracetamol). Taking into account these data, the drug committee of the Toulouse University Hospital (France) decided to withdraw Dextropropoxyphene from the hospital formulary since 1 June 2005. The aim of our study was to investigate the consequences of this withdrawal by comparing use of analgesic drugs in Toulouse University Hospital before (2004) and after (2006) Dextropropoxyphene withdrawal (using defined daily dose for 1000 hospitalization-days as the unit measure). Before withdrawal, Dextropropoxyphene (in combination with paracetamol) was the second most used analgesic drug after paracetamol alone. After Dextropropoxyphene withdrawal, total consumption of analgesic drugs decreased by 4.6% (2006 vs. 2004). There was a 28% decrease in consumption of step 2 analgesics [with an increase in oral tramadol and a slight decrease in codeine (in combination with paracetamol)]. During the same period, step 1 analgesic consumption increased by 11% (mainly paracetamol) and that of step 3 analgesics slightly decreased (-8%). These results show that Dextropropoxyphene withdrawal was not associated with a marked switch in prescriptions towards other analgesic drugs. This paper underlines the interest of a hospital-based drug committee to promote rational drug use. Finally, the present data allow us to discuss putative misuse of Dextropropoxyphene.
Pritsana Raungrut - One of the best experts on this subject based on the ideXlab platform.
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in vitro in vivo extrapolation predicts drug drug interactions arising from inhibition of codeine glucuronidation by Dextropropoxyphene fluconazole ketoconazole and methadone in humans
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Pritsana Raungrut, Verawan Uchaipichat, Benjamas Janchawee, Andrew A. Somogyi, David J. Elliot, John O MinersAbstract:Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro–in vivo extrapolation approaches were used to identify potential drug–drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant ( K m ) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S 50 values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean K m observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for Dextropropoxyphene (3.5 μM), fluconazole (202 μM), ketoconazole (0.66 μM), and methadone (0.32 μM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration–time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by Dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.
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In Vitro–In Vivo Extrapolation Predicts Drug–Drug Interactions Arising from Inhibition of Codeine Glucuronidation by Dextropropoxyphene, Fluconazole, Ketoconazole, and Methadone in Humans
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Pritsana Raungrut, Verawan Uchaipichat, Benjamas Janchawee, Andrew A. Somogyi, David J. Elliot, John O MinersAbstract:Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro–in vivo extrapolation approaches were used to identify potential drug–drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant ( K m ) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S 50 values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean K m observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for Dextropropoxyphene (3.5 μM), fluconazole (202 μM), ketoconazole (0.66 μM), and methadone (0.32 μM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration–time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by Dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.
Henry J Mcquay - One of the best experts on this subject based on the ideXlab platform.
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The Cochrane Library - Single dose oral Dextropropoxyphene, alone and with paracetamol (acetaminophen), for postoperative pain
Cochrane Database of Systematic Reviews, 1999Co-Authors: R Andrew Moore, Sally L. Collins, Jayne E Edwards, Sheena Derry, Henry J McquayAbstract:Background Patient surveys have shown that postoperative pain is often not managed well, and there is a need to assess the efficacy and safety of commonly used analgesics as newer treatments become available. Dextropropoxyphene is one example of an opioid analgesic in current use, and is widely prescribed for pain relief in combination with paracetamol under names such as Co-proxamol and Distalgesic. Objectives To determine the analgesic efficacy and adverse effects of single dose oral Dextropropoxyphene alone and in combination with paracetamol (acetaminophen) for moderate to severe postoperative pain. Search strategy Published reports were identified from: Medline (1966 - November 1996), Biological Abstracts (1985 - 1996), Embase (1980 - 1996), the Cochrane Library (Issue 4 1996), and the Oxford Pain Relief Database (1954 - 1994). Additional studies were identified from the reference lists of retrieved reports. Date of the most recent searches: July 1998. Selection criteria The inclusion criteria used were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which included Dextropropoxyphene and placebo or a combination of Dextropropoxyphene plus paracetamol and placebo. Data collection and analysis Data were extracted by two independent reviewers, and trials were quality scored. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. Main results Six trials (440 patients) compared Dextropropoxyphene with placebo and five (963 patients) compared Dextropropoxyphene plus paracetamol 650 mg with placebo. For a single dose of Dextropropoxyphene 65 mg in postoperative pain the NNT for at least 50% pain relief was 7.7 (95% confidence interval 4.6 to 22) when compared with placebo over 4-6 hours. For the equivalent dose of Dextropropoxyphene combined with paracetamol 650 mg the NNT was 4.4 (3.5 to 5.6) when compared with placebo. These results were compared with those for other analgesics obtained from equivalent systematic reviews. Pooled data showed increased incidence of central nervous system adverse effects for Dextropropoxyphene plus paracetamol compared with placebo. Reviewer's conclusions The combination of Dextropropoxyphene 65 mg with paracetamol 650 mg shows similar efficacy to tramadol 100 mg for single dose studies in postoperative pain but with a lower incidence of adverse effects. The same dose of paracetamol combined with 60 mg codeine appears more effective but, with the slight overlap in the 95% confidence intervals, this conclusion is not robust. Adverse effects of both combinations were similar. Ibuprofen 400 mg has a lower (better) NNT than both Dextropropoxyphene 65 mg plus paracetamol 650 mg and tramadol 100 mg.
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The Cochrane Library - Single dose Dextropropoxyphene, alone and with paracetamol (acetaminophen), for postoperative pain.
The Cochrane database of systematic reviews, 1999Co-Authors: Sally L. Collins, R Andrew Moore, Jayne E Edwards, Henry J McquayAbstract:Background Patient surveys have shown that postoperative pain is often not managed well, and there is a need to assess the efficacy and safety of commonly used analgesics as newer treatments become available. Dextropropoxyphene is one example of an opioid analgesic in current use, and is widely prescribed for pain relief in combination with paracetamol under names such as Co-proxamol and Distalgesic. Objectives To determine the analgesic efficacy and adverse effects of single dose oral Dextropropoxyphene alone and in combination with paracetamol (acetaminophen) for moderate to severe postoperative pain. Search strategy Published reports were identified from: Medline (1966 - November 1996), Biological Abstracts (1985 - 1996), Embase (1980 - 1996), the Cochrane Library (Issue 4 1996), and the Oxford Pain Relief Database (1954 - 1994). Additional studies were identified from the reference lists of retrieved reports. Date of the most recent searches: July 1998. Selection criteria The inclusion criteria used were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which included Dextropropoxyphene and placebo or a combination of Dextropropoxyphene plus paracetamol and placebo. Data collection and analysis Data were extracted by two independent reviewers, and trials were quality scored. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. Main results Six trials (440 patients) compared Dextropropoxyphene with placebo and five (963 patients) compared Dextropropoxyphene plus paracetamol 650 mg with placebo. For a single dose of Dextropropoxyphene 65 mg in postoperative pain the NNT for at least 50% pain relief was 7.7 (95% confidence interval 4.6 to 22) when compared with placebo over 4-6 hours. For the equivalent dose of Dextropropoxyphene combined with paracetamol 650 mg the NNT was 4.4 (3.5 to 5.6) when compared with placebo. These results were compared with those for other analgesics obtained from equivalent systematic reviews. Pooled data showed increased incidence of central nervous system adverse effects for Dextropropoxyphene plus paracetamol compared with placebo. Reviewer's conclusions The combination of Dextropropoxyphene 65 mg with paracetamol 650 mg shows similar efficacy to tramadol 100 mg for single dose studies in postoperative pain but with a lower incidence of adverse effects. The same dose of paracetamol combined with 60 mg codeine appears more effective but, with the slight overlap in the 95% confidence intervals, this conclusion is not robust. Adverse effects of both combinations were similar. Ibuprofen 400 mg has a lower (better) NNT than both Dextropropoxyphene 65 mg plus paracetamol 650 mg and tramadol 100 mg.
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single dose Dextropropoxyphene alone and with paracetamol acetaminophen for postoperative pain
Cochrane Database of Systematic Reviews, 1999Co-Authors: Sally L. Collins, R Andrew Moore, Jayne E Edwards, Henry J McquayAbstract:Background Patient surveys have shown that postoperative pain is often not managed well, and there is a need to assess the efficacy and safety of commonly used analgesics as newer treatments become available. Dextropropoxyphene is one example of an opioid analgesic in current use, and is widely prescribed for pain relief in combination with paracetamol under names such as Co-proxamol and Distalgesic. Objectives To determine the analgesic efficacy and adverse effects of single dose oral Dextropropoxyphene alone and in combination with paracetamol (acetaminophen) for moderate to severe postoperative pain. Search strategy Published reports were identified from: Medline (1966 - November 1996), Biological Abstracts (1985 - 1996), Embase (1980 - 1996), the Cochrane Library (Issue 4 1996), and the Oxford Pain Relief Database (1954 - 1994). Additional studies were identified from the reference lists of retrieved reports. Date of the most recent searches: July 1998. Selection criteria The inclusion criteria used were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which included Dextropropoxyphene and placebo or a combination of Dextropropoxyphene plus paracetamol and placebo. Data collection and analysis Data were extracted by two independent reviewers, and trials were quality scored. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. Main results Six trials (440 patients) compared Dextropropoxyphene with placebo and five (963 patients) compared Dextropropoxyphene plus paracetamol 650 mg with placebo. For a single dose of Dextropropoxyphene 65 mg in postoperative pain the NNT for at least 50% pain relief was 7.7 (95% confidence interval 4.6 to 22) when compared with placebo over 4-6 hours. For the equivalent dose of Dextropropoxyphene combined with paracetamol 650 mg the NNT was 4.4 (3.5 to 5.6) when compared with placebo. These results were compared with those for other analgesics obtained from equivalent systematic reviews. Pooled data showed increased incidence of central nervous system adverse effects for Dextropropoxyphene plus paracetamol compared with placebo. Reviewer's conclusions The combination of Dextropropoxyphene 65 mg with paracetamol 650 mg shows similar efficacy to tramadol 100 mg for single dose studies in postoperative pain but with a lower incidence of adverse effects. The same dose of paracetamol combined with 60 mg codeine appears more effective but, with the slight overlap in the 95% confidence intervals, this conclusion is not robust. Adverse effects of both combinations were similar. Ibuprofen 400 mg has a lower (better) NNT than both Dextropropoxyphene 65 mg plus paracetamol 650 mg and tramadol 100 mg.
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Single-dose Dextropropoxyphene in post-operative pain: a quantitative systematic review
European Journal of Clinical Pharmacology, 1998Co-Authors: Sally L. Collins, R Andrew Moore, Jayne E Edwards, Henry J McquayAbstract:Objective : To determine the analgesic efficacy and adverse effects of single-dose oral Dextropropoxyphene alone and in combination with paracetamol for moderate to severe post-operative pain. Methods : Published reports were identified from a variety of electronic databases including MEDLINE, Biological Abstracts, EMBASE, the Cochrane Library and the Oxford Pain Relief Database. Additional studies were identified from the reference lists of retrieved reports. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat for one patient to achieve at least 50% pain relief. Six reports (440 patients) compared Dextropropoxyphene with placebo and five (963 patients) compared Dextropropoxyphene plus paracetamol 650 mg with placebo. Results : For a single dose of Dextropropoxyphene 65 mg in post-operative pain the number-needed-to-treat for at least 50% pain relief was 7.7 (95% confidence interval 4.6 to 22) when compared with placebo over 4–6 h. For the equivalent dose of Dextropropoxyphene in combination with paracetamol 650 mg the number-needed-to-treat was 4.4 (3.5 to 5.6) when compared with placebo. Pooled data showed increased incidence of central nervous system adverse effects for Dextropropoxyphene plus paracetamol when compared with placebo. A rank order of single-dose analgesic effectiveness in post-operative pain of moderate to severe intensity obtained from similar systematic reviews is presented. Conclusion : Dextropropoxyphene 65 mg plus paracetamol 650 mg has a similar analgesic efficacy to that of tramadol 100 mg but with a lower incidence of adverse effects. Ibuprofen 400 mg has a lower (better) number-needed-to-treat than both Dextropropoxyphene 65 mg plus paracetamol 650 mg and tramadol 100 mg.
Andrew A. Somogyi - One of the best experts on this subject based on the ideXlab platform.
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in vitro in vivo extrapolation predicts drug drug interactions arising from inhibition of codeine glucuronidation by Dextropropoxyphene fluconazole ketoconazole and methadone in humans
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Pritsana Raungrut, Verawan Uchaipichat, Benjamas Janchawee, Andrew A. Somogyi, David J. Elliot, John O MinersAbstract:Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro–in vivo extrapolation approaches were used to identify potential drug–drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant ( K m ) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S 50 values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean K m observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for Dextropropoxyphene (3.5 μM), fluconazole (202 μM), ketoconazole (0.66 μM), and methadone (0.32 μM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration–time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by Dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.
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In Vitro–In Vivo Extrapolation Predicts Drug–Drug Interactions Arising from Inhibition of Codeine Glucuronidation by Dextropropoxyphene, Fluconazole, Ketoconazole, and Methadone in Humans
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Pritsana Raungrut, Verawan Uchaipichat, Benjamas Janchawee, Andrew A. Somogyi, David J. Elliot, John O MinersAbstract:Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro–in vivo extrapolation approaches were used to identify potential drug–drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant ( K m ) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S 50 values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean K m observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for Dextropropoxyphene (3.5 μM), fluconazole (202 μM), ketoconazole (0.66 μM), and methadone (0.32 μM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration–time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by Dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with Dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.
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CYP3A4 mediates Dextropropoxyphene N-demethylation to norDextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement
Xenobiotica; the fate of foreign compounds in biological systems, 2004Co-Authors: Andrew A. Somogyi, Andrew Menelaou, S. V. FullstonAbstract:1. The individual cytochrome P450 isoforms in Dextropropoxyphene N-demethylation to norDextropropoxyphene were determined and the pharmacokinetics of Dextropropoxyphene and norDextropropoxyphene in cytochrome P4502D6 (CYP2D6) extensive (EM) and poor (PM) subjects were characterized.2. Microsomes from six CYP2D6 extensive metabolizers and one CYP2D6 poor metabolizer were used with isoform specific chemical and antibody inhibitors and expressed recombinant CYP enzymes. Groups of three CYP2D6 EM and PM subjects received a single 65-mg oral dose of Dextropropoxyphene, and blood and urine were collected for 168 and 96 h, respectively.3. NorDextropropoxyphene formation in vitro was not different between the CYP2D6 extensive metabolizers (Km = 179 ± 74 μM, Clint = 0.41 ± 0.26 ml mg−1 h−1) and the PM subject (Km = 225 μM, Clint = 0.19 ml mg−1 h−1) and was catalysed predominantly by CYP3A4. There was no apparent difference in the pharmacokinetics of Dextropropoxyphene and norDextropropoxyphene in CYP2D6 EM and PM ...