The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Marilyn A Huestis - One of the best experts on this subject based on the ideXlab platform.
-
intravenous buprenorphine and Norbuprenorphine pharmacokinetics in humans
Drug and Alcohol Dependence, 2013Co-Authors: Marilyn A Huestis, Edward J Cone, S O Pirnay, Annie Umbricht, Kenzie L PrestonAbstract:Abstract Background Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine. Methods Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, Norbuprenorphine, were quantified by liquid chromatography–tandem mass spectrometry with limits of quantitation of 0.1 μg/L. Results Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3 ± 1.0, 44.5 ± 4.8, 85.2 ± 7.7, 124.6 ± 16.6, and 137.7 ± 18.8 μg/L, respectively. Maximum Norbuprenorphine concentrations occurred 10–15 min (3.7 ± 0.7 μg/L) after 16 mg IV administration. Conclusions Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2–16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg.
-
confirmatory analysis of buprenorphine Norbuprenorphine and glucuronide metabolites in plasma by lcmsms application to umbilical cord plasma from buprenorphine maintained pregnant women
Journal of Chromatography B, 2010Co-Authors: Marta Concheiro, Rolley E Johnson, Hendree E Jones, Diaa M Shakleya, Marilyn A HuestisAbstract:Abstract An LCMSMS method was developed and fully validated for the simultaneous quantification of buprenorphine (BUP), Norbuprenorphine (NBUP), buprenorphine-glucuronide (BUP-Gluc), and Norbuprenorphine-glucuronide (NBUP-Gluc) in 0.5 mL plasma, fulfilling confirmation criteria with two transitions for each compound with acceptable relative ion intensities. Transitions monitored were 468.3 > 396.2 and 468.3 > 414.3 for BUP, 414.3 > 340.1 and 414.3 > 326.0 for NBUP, 644.3 > 468.1 and 644.3 > 396.3 for BUP-Gluc, and 590.3 > 414.3 and 590.3 > 396.2 for NBUP-Gluc. Linearity was 0.1–50 ng/mL for BUP and BUP-Gluc, and 0.5–50 ng/mL for NBUP and NBUP-Gluc. Intra-day, inter-day, and total assay imprecision (%RSD) were
-
simultaneous quantification of buprenorphine Norbuprenorphine buprenorphine glucuronide and Norbuprenorphine glucuronide in human umbilical cord by liquid chromatography tandem mass spectrometry
Forensic Science International, 2009Co-Authors: Marta Concheiro, Diaa M Shakleya, Marilyn A HuestisAbstract:A LCMS method was developed and validated for the determination of buprenorphine (BUP), Norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and Norbuprenorphine glucuronide (NBUP-Gluc) in placenta. Quantification was achieved by selected ion monitoring of m/z 468.4 (BUP), 414.3 (NBUP), 644.4 (BUP-Gluc), and 590 (NBUP-Gluc). BUP and NBUP were identified monitoring MS2 fragments m/z 396, 414 and 426 for BUP, and 340, 364 and 382 for NBUP, and glucuronide conjugates monitoring MS3 fragments m/z 396 and 414 for BUP-Gluc, and 340 and 382 for NBUP-Gluc. Linearity was 1–50 ng/g. Intra-day, inter-day and total assay imprecision (% RSD) were <13.4%, and analytical recoveries were 96.2–113.1%. Extraction efficiencies ranged from 40.7–68%, process efficiencies 38.8–70.5%, and matrix effect 1.3–15.4%. Limits of detection were 0.8 ng/g for all compounds. An authentic placenta from an opioid-dependent pregnant woman receiving BUP pharmacotherapy was analyzed. BUP was not detected but metabolite concentrations were NBUP-Gluc 46.6, NBUP 15.7 and BUP-Gluc 3.2 ng/g.
-
urinary excretion of buprenorphine Norbuprenorphine buprenorphine glucuronide and Norbuprenorphine glucuronide in pregnant women receiving buprenorphine maintenance treatment
Clinical Chemistry, 2009Co-Authors: Sherri L. Kacinko, Hendree E Jones, Rolley E Johnson, Robin E Choo, Marta Concheiroguisan, Marilyn A HuestisAbstract:Background: Buprenorphine (BUP) is under investigation as a medication therapy for opioid-dependent pregnant women. We investigated BUP and metabolite disposition in urine from women maintained on BUP during the second and third trimesters of pregnancy and postpartum. Methods: We measured BUP, Norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and NBUP-Gluc concentrations in 515 urine specimens collected thrice weekly from 9 women during pregnancy and postpartum. Specimens were analyzed using a fully validated liquid chromatography-mass spectrometry method with limits of quantification of 5 μg/L for BUP and BUP-Gluc and 25 μg/L for NBUP and its conjugated metabolite. We examined ratios of metabolites across trimesters and postpartum to identify possible changes in metabolism during pregnancy. Results: NBUP-Gluc was the primary metabolite identified in urine and exceeded BUP-Gluc concentrations in 99% of specimens. Whereas BUP-Gluc was identified in more specimens than NBUP, NBUP exceeded BUP-Gluc concentrations in 77.9% of specimens that contained both analytes. Among all participants, the mean BUP-Gluc:NBUP-Gluc ratio was significantly higher in the second trimester compared to the third trimester, and there were significant intrasubject differences between trimesters in 71% of participants. In 3 women, the percent daily dose excreted was higher during pregnancy than postpregnancy, consistent with other data indicating increased renal elimination of drugs during pregnancy. Conclusions: These data are the first to evaluate urinary disposition of BUP and metabolites in a cohort of pregnant women. Variable BUP excretion during pregnancy may indicate metabolic changes requiring dose adjustment during later stages of gestation. .
-
simultaneous quantification of buprenorphine Norbuprenorphine buprenorphine glucuronide and Norbuprenorphine glucuronide in human placenta by liquid chromatography mass spectrometry
Analytical and Bioanalytical Chemistry, 2009Co-Authors: Marta Concheiroguisan, Diaa M Shakleya, Marilyn A HuestisAbstract:A LCMS method was developed and validated for the determination of buprenorphine (BUP), Norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and Norbuprenorphine glucuronide (NBUP-Gluc) in placenta. Quantification was achieved by selected ion monitoring of m/z 468.4 (BUP), 414.3 (NBUP), 644.4 (BUP-Gluc), and 590 (NBUP-Gluc). BUP and NBUP were identified monitoring MS2 fragments m/z 396, 414 and 426 for BUP, and 340, 364 and 382 for NBUP, and glucuronide conjugates monitoring MS3 fragments m/z 396 and 414 for BUP-Gluc, and 340 and 382 for NBUP-Gluc. Linearity was 1–50 ng/g. Intra-day, inter-day and total assay imprecision (% RSD) were <13.4%, and analytical recoveries were 96.2–113.1%. Extraction efficiencies ranged from 40.7–68%, process efficiencies 38.8–70.5%, and matrix effect 1.3–15.4%. Limits of detection were 0.8 ng/g for all compounds. An authentic placenta from an opioid-dependent pregnant woman receiving BUP pharmacotherapy was analyzed. BUP was not detected but metabolite concentrations were NBUP-Gluc 46.6, NBUP 15.7 and BUP-Gluc 3.2 ng/g.
David E Moody - One of the best experts on this subject based on the ideXlab platform.
-
Interaction between buprenorphine and atazanavir [oral abstract
2015Co-Authors: Elinore F Mccance-katz, David E Moody, Gene D Morse, Patricia Pade, Gerald Friedl, Petrie M RaineyAbstract:Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-hour sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and Mini-Mental State Examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), Norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001)
-
patterns of free unconjugated buprenorphine Norbuprenorphine and their glucuronides in urine using liquid chromatography tandem mass spectrometry
Journal of Analytical Toxicology, 2012Co-Authors: Gwendolyn A Mcmillin, Rebecka Davis, Heidi J Carlisle, Chantry J Clark, Stephanie J Marin, David E MoodyAbstract:Patterns of buprenorphine and metabolites were examined in 1946 positive urine samples analyzed by liquid chromatography-tandem mass spectrometry for free (unconjugated) buprenorphine and Norbuprenorphine (quantitative, 2 to 1000 ng/mL) and buprenorphine-glucuronide (B3G) and Norbuprenorphine-glucuronide (N3G) (semi-quantitative, 5 to 1000 ng/mL). Two distribution patterns predominated with 49.1% positive for Norbuprenorphine, B3G, and N3G and 41.6% positive for buprenorphine, Norbuprenorphine, B3G, and N3G. Buprenorphine, positive in 45.5% of samples, was mostly 1000 ng/mL. Norbuprenorphine, B3G, and N3G had semi-Gaussian distributions with medians of 64.7, 108, and 432 ng/mL, respectively. With buprenorphine 1000 ng/mL" buprenorphine samples, free buprenorphine was 4160 to 39,400 ng/mL and free naloxone 2140 to 9560 ng/mL. In 87 subsequent samples with buprenorphine 100 ng/mL (particularly with low metabolite concentrations) are suspect of urine adulteration with medication (4% in the database) that can be checked in most cases by concurrent analysis for naloxone.
-
glucuronidation of buprenorphine and Norbuprenorphine by human liver microsomes and udp glucuronosyltransferases
Drug Metabolism Letters, 2009Co-Authors: Yan Chang, David E MoodyAbstract:We investigated the enzyme kinetics of buprenorphine and Norbuprenorphine glucuronidation in human liver microsomes and UDP-glucuronosyltransferase (UGT) Supersomes. The involvement of UGT 1A1, 1A3 and 2B7 in buprenorpine and 1A3 in Norbuprenorphine glucuronidation were confirmed. Novel involvement of 2B17 with buprenorphine and 1A1 with Norbuprenorphine were demonstrated. Scaling of buprenorphine clearance with, or without, correction for the nonspecific microsomal protein binding of buprenorphine (f(u) = 0.42) suggested glucuronidation was a significant route for hepatic clearance of buprenorphine.
-
interaction between buprenorphine and atazanavir or atazanavir ritonavir
Drug and Alcohol Dependence, 2007Co-Authors: Elinore F Mccancekatz, Gerald Friedland, David E Moody, Gene D Morse, Robin Difrancesco, Patricia Pade, Petrie M RaineyAbstract:Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-h sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400mg daily) or atazanavir/ritonavir (300/100mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and mini-mental state examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), Norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and Norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.
-
the in vivo glucuronidation of buprenorphine and Norbuprenorphine determined by liquid chromatography electrospray ionization tandem mass spectrometry
Therapeutic Drug Monitoring, 2006Co-Authors: Wei Huang, David E Moody, Elinore F MccancekatzAbstract:The opioid partial agonist medication, buprenorphine (BUP), and its primary metabolite, Norbuprenorphine (NBUP), are extensively glucuronidated. Sensitive analytical methods that include determination of buprenorphine-3-glucuronide (BUPG) and Norbuprenorphine-3-glucuronide (NBUPG) are needed to more fully understand the metabolism and pharmacokinetics of buprenorphine. A method has now been developed that uses solid-phase extraction followed by liquid chromatography-electrospray ionization-tandem mass spectrometry. BUP-d4, NBUP-d3, and morphine-3-glucuronide-d3 were used as internal standards. The lower limit of quantitation was 0.1 and 0.5 ng/mL for each of the analytes in 1-mL of human plasma and urine, respectively, except for NBUP in urine in which it was 2.5 ng/mL. The analytes were stable under the following conditions: plasma and urine at room temperature, up to 20 hours; plasma and urine at -20 degrees C for 119 and 85 days, respectively; plasma freeze-thaw, up to 3 cycles; processed sample, up to 96 hours at -20 degrees C and up to 48 hours on the autosampler; stock solutions at room temperature and at -20 degrees C, up to 6 hours and 128 days, respectively. In plasma collected from 5 subjects on maintenance daily sublingual doses of 16 mg BUP and 4 mg naloxone, respective 0- to 24-hour areas under the curve were 32, 88, 26, and 316 ng/mL x h for BUP, NBUP, BUPG, and NBUPG. In urine samples respective percent of daily dose excreted in the 24-hour urine were 0.014%, 1.89%, 1.01%, and 7.76%. This method allowed us to determine that NBUPG is a major metabolite present in plasma and urine of BUP. Because urinary elimination is limited ( approximately 11% of daily dose), the role of NBUPG in total clearance of buprenorphine is not yet known.
Elinore F Mccancekatz - One of the best experts on this subject based on the ideXlab platform.
-
interaction between buprenorphine and atazanavir or atazanavir ritonavir
Drug and Alcohol Dependence, 2007Co-Authors: Elinore F Mccancekatz, Gerald Friedland, David E Moody, Gene D Morse, Robin Difrancesco, Patricia Pade, Petrie M RaineyAbstract:Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-h sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400mg daily) or atazanavir/ritonavir (300/100mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and mini-mental state examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), Norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and Norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.
-
the in vivo glucuronidation of buprenorphine and Norbuprenorphine determined by liquid chromatography electrospray ionization tandem mass spectrometry
Therapeutic Drug Monitoring, 2006Co-Authors: Wei Huang, David E Moody, Elinore F MccancekatzAbstract:The opioid partial agonist medication, buprenorphine (BUP), and its primary metabolite, Norbuprenorphine (NBUP), are extensively glucuronidated. Sensitive analytical methods that include determination of buprenorphine-3-glucuronide (BUPG) and Norbuprenorphine-3-glucuronide (NBUPG) are needed to more fully understand the metabolism and pharmacokinetics of buprenorphine. A method has now been developed that uses solid-phase extraction followed by liquid chromatography-electrospray ionization-tandem mass spectrometry. BUP-d4, NBUP-d3, and morphine-3-glucuronide-d3 were used as internal standards. The lower limit of quantitation was 0.1 and 0.5 ng/mL for each of the analytes in 1-mL of human plasma and urine, respectively, except for NBUP in urine in which it was 2.5 ng/mL. The analytes were stable under the following conditions: plasma and urine at room temperature, up to 20 hours; plasma and urine at -20 degrees C for 119 and 85 days, respectively; plasma freeze-thaw, up to 3 cycles; processed sample, up to 96 hours at -20 degrees C and up to 48 hours on the autosampler; stock solutions at room temperature and at -20 degrees C, up to 6 hours and 128 days, respectively. In plasma collected from 5 subjects on maintenance daily sublingual doses of 16 mg BUP and 4 mg naloxone, respective 0- to 24-hour areas under the curve were 32, 88, 26, and 316 ng/mL x h for BUP, NBUP, BUPG, and NBUPG. In urine samples respective percent of daily dose excreted in the 24-hour urine were 0.014%, 1.89%, 1.01%, and 7.76%. This method allowed us to determine that NBUPG is a major metabolite present in plasma and urine of BUP. Because urinary elimination is limited ( approximately 11% of daily dose), the role of NBUPG in total clearance of buprenorphine is not yet known.
Gwendolyn A Mcmillin - One of the best experts on this subject based on the ideXlab platform.
-
quantitation of total buprenorphine and Norbuprenorphine in meconium by lc ms ms
Methods of Molecular Biology, 2016Co-Authors: Stephanie J Marin, Gwendolyn A McmillinAbstract:Buprenorphine (Suboxone, Zubsolv, Buprenex, Butrans, etc.) is an opioid drug that has been used to treat opioid dependence on an outpatient basis, and is also prescribed for managing moderate to severe pain. Pregnant women may be prescribed buprenorphine as part of a treatment plan for opioid addiction. This chapter quantitates buprenorphine and Norbuprenorphine in meconium by liquid chromatography tandem mass spectrometry (LC-MS/MS).
-
quantitation of buprenorphine Norbuprenorphine buprenorphine glucuronide Norbuprenorphine glucuronide and naloxone in urine by lc ms ms
Methods of Molecular Biology, 2016Co-Authors: Stephanie J Marin, Gwendolyn A McmillinAbstract:Buprenorphine is an opioid drug that has been used to treat opioid dependence on an outpatient basis, and is also prescribed for managing moderate to severe pain. Some formulations of buprenorphine also contain naloxone to discourage misuse. The major metabolite of buprenorphine is Norbuprenorphine. Both compounds are pharmacologically active and both are extensively metabolized to their glucuronide conjugates, which are also active metabolites. Direct quantitation of the glucuronide conjugates in conjunction with free buprenorphine, Norbuprenorphine, and naloxone in urine can distinguish compliance with prescribed therapy from specimen adulteration intended to mimic compliance with prescribed buprenorphine. This chapter quantitates buprenorphine, Norbuprenorphine, their glucuronide conjugates and naloxone directly in urine by liquid chromatography tandem mass spectrometry (LC-MS/MS). Urine is pretreated with formic acid and undergoes solid phase extraction (SPE) prior to analysis by LC-MS/MS.
-
patterns of free unconjugated buprenorphine Norbuprenorphine and their glucuronides in urine using liquid chromatography tandem mass spectrometry
Journal of Analytical Toxicology, 2012Co-Authors: Gwendolyn A Mcmillin, Rebecka Davis, Heidi J Carlisle, Chantry J Clark, Stephanie J Marin, David E MoodyAbstract:Patterns of buprenorphine and metabolites were examined in 1946 positive urine samples analyzed by liquid chromatography-tandem mass spectrometry for free (unconjugated) buprenorphine and Norbuprenorphine (quantitative, 2 to 1000 ng/mL) and buprenorphine-glucuronide (B3G) and Norbuprenorphine-glucuronide (N3G) (semi-quantitative, 5 to 1000 ng/mL). Two distribution patterns predominated with 49.1% positive for Norbuprenorphine, B3G, and N3G and 41.6% positive for buprenorphine, Norbuprenorphine, B3G, and N3G. Buprenorphine, positive in 45.5% of samples, was mostly 1000 ng/mL. Norbuprenorphine, B3G, and N3G had semi-Gaussian distributions with medians of 64.7, 108, and 432 ng/mL, respectively. With buprenorphine 1000 ng/mL" buprenorphine samples, free buprenorphine was 4160 to 39,400 ng/mL and free naloxone 2140 to 9560 ng/mL. In 87 subsequent samples with buprenorphine 100 ng/mL (particularly with low metabolite concentrations) are suspect of urine adulteration with medication (4% in the database) that can be checked in most cases by concurrent analysis for naloxone.
Evan D. Kharasch - One of the best experts on this subject based on the ideXlab platform.
-
high sensitivity analysis of buprenorphine Norbuprenorphine buprenorphine glucuronide and Norbuprenorphine glucuronide in plasma and urine by liquid chromatography mass spectrometry
Analytical Abstracts, 2013Co-Authors: Karen J. Regina, Evan D. KharaschAbstract:A new method using ultra-fast liquid chromatography and tandem mass spectrometry (UFLC-MS/MS) was developed for the simultaneous determination of buprenorphine and the metabolites Norbuprenorphine, buprenorphine-3β-glucuronide, and Norbuprenorphine-3β-glucuronide in plasma and urine. Sample handling, sample preparation and solid-phase extraction procedures were optimized for maximum analyte recovery. All four analytes of interest were quantified by positive ion electrospray ionization tandem mass spectrometry after solid-phase microextraction. The lower limits of quantification in plasma were 1 pg/mL for buprenorphine and buprenorphine glucuronide, and 10 pg/mL for Norbuprenorphine and Norbuprenorphine glucuronide. The lower limits of quantitation in urine were 10 pg/mL for buprenorphine, Norbuprenorphine and their glucuronides. Overall extraction recoveries ranged from 68-100% in both matrices. Interassay precision and accuracy was within 10% for all four analytes in plasma and within 15% in urine. The method was applicable to pharmacokinetic studies of low-dose buprenorphine.
-
P-Glycoprotein Is a Major Determinant of Norbuprenorphine Brain Exposure and Antinociception
The Journal of pharmacology and experimental therapeutics, 2012Co-Authors: Sarah M. Brown, Scott D. Campbell, Amanda Crafford, Karen J. Regina, Michael J. Holtzman, Evan D. KharaschAbstract:Norbuprenorphine is a major metabolite of buprenorphine and potent agonist of μ, δ, and κ opioid receptors. Compared with buprenorphine, Norbuprenorphine causes minimal antinociception but greater respiratory depression. It is unknown whether the limited antinociception is caused by low efficacy or limited brain exposure. Norbuprenorphine is an in vitro substrate of the efflux transporter P-glycoprotein (Mdr1), but the role of P-glycoprotein in Norbuprenorphine transport in vivo is unknown. This investigation tested the hypothesis that limited Norbuprenorphine antinociception results from P-glycoprotein-mediated efflux and limited brain access. Human P-glycoprotein-mediated transport in vitro of buprenorphine, Norbuprenorphine, and their respective glucuronide conjugates was assessed by using transfected cells. P-glycoprotein-mediated Norbuprenorphine transport and consequences in vivo were assessed by using mdr1a(+/+) and mdr1a(−/−) mice. Antinociception was determined by hot-water tail-flick assay, and respiratory effects were determined by unrestrained whole-body plethysmography. Brain and plasma Norbuprenorphine and Norbuprenorphine-3-glucuronide were quantified by mass spectrometry. In vitro, the net P-glycoprotein-mediated efflux ratio for Norbuprenorphine was nine, indicating significant efflux. In contrast, the efflux ratio for buprenorphine and the two glucuronide conjugates was unity, indicating absent transport. The Norbuprenorphine brain/plasma concentration ratio was significantly greater in mdr1a(−/−) than mdr1a(+/+) mice. The magnitude and duration of Norbuprenorphine antinociception were significantly increased in mdr1a(−/−) compared with mdr1a(+/+) mice, whereas the reduction in respiratory rate was similar. Results show that Norbuprenorphine is an in vitro and in vivo substrate of P-glycoprotein. P-glycoprotein-mediated efflux influences brain access and antinociceptive, but not the respiratory, effects of Norbuprenorphine.
-
Buprenorphine metabolites, buprenorphine-3-glucuronide and Norbuprenorphine-3-glucuronide, are biologically active.
Anesthesiology, 2011Co-Authors: Sarah M. Brown, Michael J. Holtzman, Thomas Kim, Evan D. KharaschAbstract:Background: The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites Norbuprenorphine, buprenorphine-3-glucuronide, and Norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and Norbuprenorphine. Methods: Competitive inhibition of radioligand binding to human,, and opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in SwissWebster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing. Results: Buprenorphine-3-glucuronide had high affinity for human (Ki [inhibition constant] 4.9 2.7 pM), (Ki 270 0.4 nM), and nociceptin (Ki 36 0.3 M) but not receptors. Norbuprenorphine-3-glucuronide had affinity for human (Ki 300 0.5 nM) and nociceptin (Ki 18 0.2 M) but not or receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but Norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation. Conclusions: Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures, which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.
-
chemical and enzyme assisted syntheses of Norbuprenorphine 3 β d glucuronide
Bioconjugate Chemistry, 2011Co-Authors: Jinda Fan, Sarah M. Brown, Evan D. KharaschAbstract:Norbuprenorphine-3-β-d-glucuronide (nBPN-3-β-d-G, 1) is a major phase II metabolite of buprenorphine, a pharmaceutical used for the treatment of opioid addiction. The pharmacological activity of compound 1 is not clear because investigations have been limited by the lack of chemically pure, well characterized 1 in sufficient quantities for in vitro and in vivo experiments. This work describes two concise, new methods of synthesis of 1, a chemical and an enzyme-assisted synthesis. The chemical synthesis used a strategy based on a combination of Koenig-Knorr coupling and amino-silyl protection. The enzyme-assisted synthesis used dog liver to convert the substrate Norbuprenorphine (nBPN, 2) to 1. Both methods provided 1, characterized by (1)H NMR and tandem mass spectrometry, with purity >96%. The fractional yield of the enzyme-assisted synthesis was greater than that of the chemical synthesis (67% vs 5.3%), but due to larger reaction volumes, the chemical synthesis afforded greater amounts of total 1.
