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Frank Skorpen - One of the best experts on this subject based on the ideXlab platform.
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a novel functional polymorphism in the uridine diphosphate glucuronosyltransferase 2b7 promoter with significant impact on promoter activity
Clinical Pharmacology & Therapeutics, 2004Co-Authors: Frank Skorpen, Yannick Duguay, Cecilie Baar, Chantal GuillemetteAbstract:To clarify the molecular determinants of the metabolic variability of Morphine, we searched for genetic polymorphisms in the gene for uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) and evaluated their functional impact in vitro and in patients with cancer receiving long-term Morphine therapy. Genetic analysis revealed the existence of 8 single-nucleotide polymorphisms (SNPs), 6 of which are tightly linked and are at positions -1248, -1241, -1054, -842, -268, and -102 relative to the hepatic start site. In contrast, an SNP at position -66 occurs independently, whereas a novel variation at position -79 appears to be in linkage disequilibrium with the codon 268 SNP (UGT2B7*2). At least 4 haplotypes were observed in white subjects included in the initial SNP screening. On functional in vitro characterization, promoter-reporter gene constructs with the -79 variation displayed 2.5- to 7-fold less activity compared with the wild-type construct in Caco-2 colon cells and HepG2 hepatoma cells, respectively (P =.015 and P <.001, respectively). To investigate a possible effect of the -79 variation in vivo, serum Morphine and Morphine Glucuronide concentrations were measured by liquid chromatography-mass spectrometry in patients with cancer who received long-term oral Morphine therapy, and subjects were then genotyped for the -79 polymorphism. Among 175 patients with normal hepatic and renal function, 6 were heterozygous for the -79 variation, and the Morphine-6-Glucuronide (M6G)/Morphine and Morphine-3-Glucuronide (M3G)/Morphine ratios versus those in the 169 noncarriers were 5.9 +/- 3.5 versus 7.1 +/- 7.0 for M6G/Morphine (P =.96) and 31.2 +/- 17.1 versus 42.9 +/- 31.2 for M3G/Morphine (P =.53), respectively. Further studies in larger samples are needed to make conclusions about the possible clinical relevance of the -79 polymorphism in the UGT2B7 gene.
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Morphine Glucuronide to Morphine plasma ratios are unaffected by the ugt2b7 h268y and ugt1a1 28 polymorphisms in cancer patients on chronic Morphine therapy
European Journal of Clinical Pharmacology, 2002Co-Authors: Monica Holthe, Pal Klepstad, Kolbjorn Zahlsen, Petter C Borchgrevink, Lars Hagen, Ola Dale, Stein Kaasa, Hans E Krokan, Frank SkorpenAbstract:Abstract Objective. UDP-glucuronosyltransferase (UGT) 2B7 is the major UGT isoform responsible for the 3- and 6-glucuronidation of Morphine in humans. Studies in rats have indicated that UGT1A1 may also contribute to the formation of Morphine 3-Glucuronide (M3G). Our objective was to investigate whether the UGT2B7 H268Y and UGT1A1*28 polymorphisms contribute to the variability in Morphine Glucuronide-to-Morphine plasma ratios among cancer patients undergoing analgesic therapy with Morphine. Methods. Seventy patients with normal hepatic and renal function using slow-release Morphine to relieve cancer pain were included. UGT2B7 genotyping was performed using restriction enzyme analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Wild-type and variant alleles of the UGT1A1 gene were identified using sizing of PCR-amplified fragments. Morphine 6-Glucuronide (M6G)/Morphine, M3G/Morphine, and M3G/M6G plasma ratios were compared between genotypes. Results. The M3G/Morphine, M6G/Morphine, and M3G/M6G plasma ratios varied 16-, 42-, and sevenfold, respectively, among individuals. No statistically significant differences in plasma ratios were found between individuals possessing UGT2B7 H/H (n=20), H/Y (n=30), or Y/Y (n=20) genotypes. Five patients were homozygous for the UGT1A1 TA7 allele, which is associated with reduced UGT1A1 gene expression. However, the mean M3G/M6G and M3G/Morphine plasma ratios in TA7 homozygous subjects did not differ significantly from those of heterozygous or homozygous wild-type (TA6) individuals. Conclusion. The UGT2B7 H268Y polymorphism cannot account for the considerable variation in Glucuronide-to-Morphine ratios in cancer patients. Moreover, the contribution of UGT1A1 to the formation of M3G appears to be of minor biological significance, at least in a UGT2B7 background.
Chantal Guillemette - One of the best experts on this subject based on the ideXlab platform.
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a novel functional polymorphism in the uridine diphosphate glucuronosyltransferase 2b7 promoter with significant impact on promoter activity
Clinical Pharmacology & Therapeutics, 2004Co-Authors: Frank Skorpen, Yannick Duguay, Cecilie Baar, Chantal GuillemetteAbstract:To clarify the molecular determinants of the metabolic variability of Morphine, we searched for genetic polymorphisms in the gene for uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) and evaluated their functional impact in vitro and in patients with cancer receiving long-term Morphine therapy. Genetic analysis revealed the existence of 8 single-nucleotide polymorphisms (SNPs), 6 of which are tightly linked and are at positions -1248, -1241, -1054, -842, -268, and -102 relative to the hepatic start site. In contrast, an SNP at position -66 occurs independently, whereas a novel variation at position -79 appears to be in linkage disequilibrium with the codon 268 SNP (UGT2B7*2). At least 4 haplotypes were observed in white subjects included in the initial SNP screening. On functional in vitro characterization, promoter-reporter gene constructs with the -79 variation displayed 2.5- to 7-fold less activity compared with the wild-type construct in Caco-2 colon cells and HepG2 hepatoma cells, respectively (P =.015 and P <.001, respectively). To investigate a possible effect of the -79 variation in vivo, serum Morphine and Morphine Glucuronide concentrations were measured by liquid chromatography-mass spectrometry in patients with cancer who received long-term oral Morphine therapy, and subjects were then genotyped for the -79 polymorphism. Among 175 patients with normal hepatic and renal function, 6 were heterozygous for the -79 variation, and the Morphine-6-Glucuronide (M6G)/Morphine and Morphine-3-Glucuronide (M3G)/Morphine ratios versus those in the 169 noncarriers were 5.9 +/- 3.5 versus 7.1 +/- 7.0 for M6G/Morphine (P =.96) and 31.2 +/- 17.1 versus 42.9 +/- 31.2 for M3G/Morphine (P =.53), respectively. Further studies in larger samples are needed to make conclusions about the possible clinical relevance of the -79 polymorphism in the UGT2B7 gene.
Yannick Duguay - One of the best experts on this subject based on the ideXlab platform.
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a novel functional polymorphism in the uridine diphosphate glucuronosyltransferase 2b7 promoter with significant impact on promoter activity
Clinical Pharmacology & Therapeutics, 2004Co-Authors: Frank Skorpen, Yannick Duguay, Cecilie Baar, Chantal GuillemetteAbstract:To clarify the molecular determinants of the metabolic variability of Morphine, we searched for genetic polymorphisms in the gene for uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) and evaluated their functional impact in vitro and in patients with cancer receiving long-term Morphine therapy. Genetic analysis revealed the existence of 8 single-nucleotide polymorphisms (SNPs), 6 of which are tightly linked and are at positions -1248, -1241, -1054, -842, -268, and -102 relative to the hepatic start site. In contrast, an SNP at position -66 occurs independently, whereas a novel variation at position -79 appears to be in linkage disequilibrium with the codon 268 SNP (UGT2B7*2). At least 4 haplotypes were observed in white subjects included in the initial SNP screening. On functional in vitro characterization, promoter-reporter gene constructs with the -79 variation displayed 2.5- to 7-fold less activity compared with the wild-type construct in Caco-2 colon cells and HepG2 hepatoma cells, respectively (P =.015 and P <.001, respectively). To investigate a possible effect of the -79 variation in vivo, serum Morphine and Morphine Glucuronide concentrations were measured by liquid chromatography-mass spectrometry in patients with cancer who received long-term oral Morphine therapy, and subjects were then genotyped for the -79 polymorphism. Among 175 patients with normal hepatic and renal function, 6 were heterozygous for the -79 variation, and the Morphine-6-Glucuronide (M6G)/Morphine and Morphine-3-Glucuronide (M3G)/Morphine ratios versus those in the 169 noncarriers were 5.9 +/- 3.5 versus 7.1 +/- 7.0 for M6G/Morphine (P =.96) and 31.2 +/- 17.1 versus 42.9 +/- 31.2 for M3G/Morphine (P =.53), respectively. Further studies in larger samples are needed to make conclusions about the possible clinical relevance of the -79 polymorphism in the UGT2B7 gene.
M L Slevin - One of the best experts on this subject based on the ideXlab platform.
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the pharmacokinetics of Morphine and Morphine Glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of Morphine
British Journal of Clinical Pharmacology, 2000Co-Authors: R Stuartharris, Simon P Joel, P Mcdonald, David C Currow, M L SlevinAbstract:Aims To investigate the pharmacokinetics of Morphine, Morphine-6-Glucuronide (M6G) and Morphine-3-Glucuronide (M3G) in healthy volunteers after the administration of Morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c.i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of Morphine. Methods Six healthy volunteers each received 5 mg Morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for Morphine, M6G and M3G. Results After i.v. Morphine, the concentrations of Morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l− 1, for a 10 mg dose to a 70 kg subject). After s.c.b. Morphine, similar results were obtained except that the median tmax values for Morphine and M3G were significantly longer than after i.v. Morphine (P< 0.001 and P< 0.05, respectively), with a trend to a longer tmax for M6G (P= 0.09). The appearance half-lives after s.c.b. Morphine for M6G and M3G were also significantly longer than after i.v. Morphine (P= 0.03 and P< 0.05, respectively). Comparison of log-transformed AUC values indicated that i.v. and s.c.b. administration of Morphine were bioequivalent with respect to Morphine, M6G and M3G. In comparison with i.v. Morphine, Morphine by s.c.i. was associated with significantly longer median tmax values for Morphine (P< 0.001), M6G (P< 0.001) and M3G (P< 0.05), and the mean standardized Cmax values significantly lower than after both i.v. and s.c.b. Morphine (Morphine P< 0.001, M6G P< 0.001 and M3G P< 0.01 for each comparison). Comparison of log-transformed AUC values after i.v. and s.c.i. Morphine indicated that the two routes were not bioequivalent for Morphine (log-transformed AUC ratio 0.78, 90% CI 0.66–0.93), M6G (0.72, 90% CI 0.63–0.82), or M3G (0.65, 90% CI 0.54–0.78). A small stability study indicated no evidence of adsorptive losses from Morphine infused over 4 h using the infusion devices from the study. Conclusions Although bioequivalence was demonstrated between the s.c.b. and i.v. routes of Morphine administration, the bioavailabilities of Morphine, M6G and M3G after s.c.i. were significantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of Morphine.
Peter R Chai - One of the best experts on this subject based on the ideXlab platform.
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Rapid Assessment of Opioid Exposure and Treatment in Cities Through Robotic Collection and Chemical Analysis of Wastewater
Journal of Medical Toxicology, 2020Co-Authors: Norkio Endo, Newsha Ghaeli, Claire Duvallet, Katelyn Foppe, Timothy B Erickson, Mariana Matus, Peter R ChaiAbstract:Introduction Accurate data regarding opioid use, overdose, and treatment is important in guiding community efforts at combating the opioid epidemic. Wastewater-based epidemiology (WBE) is a potential method to quantify community-level trends of opioid exposure beyond overdose data, which is the basis of most existing response efforts. However, most WBE efforts collect parent opioid compounds (e.g., Morphine) at wastewater treatment facilities, measuring opioid concentrations across large catchment zones which typically represent an entire municipality. We sought to deploy a robotic sampling device at targeted manholes within a city to semi-quantitatively detect opioid metabolites (e.g., Morphine Glucuronide) at a sub-city community resolution. Methods We deployed a robotic wastewater sampling platform at ten residential manholes in an urban municipality in North Carolina, accounting for 44.5% of the total municipal population. Sampling devices comprised a robotic sampling arm with in situ solid phase extraction, and collected hourly samples over 24-hour periods. We used targeted mass spectrometry to detect the presence of a custom panel of opioids, naloxone, and buprenorphine. Results Ten sampling sites were selected to be a representative survey of the entire municipality by integrating sewer network and demographic GIS data. All eleven metabolites targeted were detected during the program. The average Morphine milligram equivalent (MME) across the nine illicit and prescription opioids, as excreted and detected in wastewater, was 49.1 (standard deviation of 31.9) MME/day/1000-people. Codeine was detected most frequently (detection rate of 100%), and buprenorphine was detected least frequently (12%). The presence of naloxone correlated with city data of known overdoses reversed by emergency medical services in the prehospital setting. Conclusion Wastewater-based epidemiology with smart sewer selection and robotic wastewater collection is feasible to detect the presence of specific opioids, naloxone, methadone, and buprenorphine within a city. These results suggest that wastewater epidemiology could be used to detect patterns of opioid exposure and may ultimately provide information for opioid use disorder (OUD) treatment and harm reduction programs.
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rapid assessment of opioid exposure and treatment in cities through robotic collection and chemical analysis of wastewater
Journal of Medical Toxicology, 2020Co-Authors: Norkio Endo, Newsha Ghaeli, Claire Duvallet, Katelyn Foppe, Timothy B Erickson, Mariana Matus, Peter R ChaiAbstract:Accurate data regarding opioid use, overdose, and treatment is important in guiding community efforts at combating the opioid epidemic. Wastewater-based epidemiology (WBE) is a potential method to quantify community-level trends of opioid exposure beyond overdose data, which is the basis of most existing response efforts. However, most WBE efforts collect parent opioid compounds (e.g., Morphine) at wastewater treatment facilities, measuring opioid concentrations across large catchment zones which typically represent an entire municipality. We sought to deploy a robotic sampling device at targeted manholes within a city to semi-quantitatively detect opioid metabolites (e.g., Morphine Glucuronide) at a sub-city community resolution. We deployed a robotic wastewater sampling platform at ten residential manholes in an urban municipality in North Carolina, accounting for 44.5% of the total municipal population. Sampling devices comprised a robotic sampling arm with in situ solid phase extraction, and collected hourly samples over 24-hour periods. We used targeted mass spectrometry to detect the presence of a custom panel of opioids, naloxone, and buprenorphine. Ten sampling sites were selected to be a representative survey of the entire municipality by integrating sewer network and demographic GIS data. All eleven metabolites targeted were detected during the program. The average Morphine milligram equivalent (MME) across the nine illicit and prescription opioids, as excreted and detected in wastewater, was 49.1 (standard deviation of 31.9) MME/day/1000-people. Codeine was detected most frequently (detection rate of 100%), and buprenorphine was detected least frequently (12%). The presence of naloxone correlated with city data of known overdoses reversed by emergency medical services in the prehospital setting. Wastewater-based epidemiology with smart sewer selection and robotic wastewater collection is feasible to detect the presence of specific opioids, naloxone, methadone, and buprenorphine within a city. These results suggest that wastewater epidemiology could be used to detect patterns of opioid exposure and may ultimately provide information for opioid use disorder (OUD) treatment and harm reduction programs.