The In Vivo Glucuronidation of Buprenorphine and Norbuprenorphine Determined by Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry

Huang, Wei; Moody, David E.; McCance‐Katz, Elinore F.

doi:10.1097/01.ftd.0000197094.92559.b4

Cited by 71 publications

(90 citation statements)

References 22 publications

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“…2.6.1 Buprenorphine assay-Buprenorphine and metabolite concentrations were determined using a recently described liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (Huang et al, 2006). Briefly, buprenorphine-d 4 and norbuprenorphine-d 3 were added to samples as the internal standards.…”

Section: Biochemical Assaysmentioning

confidence: 99%

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

McCance‐Katz

Moody

Morse

et al. 2007

Drug and Alcohol Dependence

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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/naloxonemaintained, 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), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxonemaintained 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.

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Section: Biochemical Assaysmentioning

confidence: 99%

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

McCance‐Katz

Moody

Morse

et al. 2007

Drug and Alcohol Dependence

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“…MS/MS conditions used were 3.0 mTorr argon collision gas and 45 eV collision potential. When the Quantum was used, we found that norbuprenorphine had better sensitivity when the survivor molecular ion was monitored (i.e., 22 eV collision potential with m/z 414 to m/z 414) (Huang et al, 2006). The liquid chromatograph was a Hewlett-Packard Series 1100 HPLC (Agilent Technologies, Palo Alto, CA).…”

Section: Methodsmentioning

confidence: 99%

“…The smaller difference between hydrolyzed M3 and nonhydrolyzed M3 (mean ϭ 68.5%, range 53-100% of unconjugated) suggests that it is excreted, for the most part, as the unconjugated form (Table 4). Nonhydrolyzed urine was also extracted by solid-phase extraction (Huang et al, 2006) to directly examine the conjugated buprenorphine and metabolites. Neutral loss scans of 176 (glucuronide conjugates) and 80 (sulfonate conjugates), and SRM (transition of molecular ion of interest to Ϫ176 and Ϫ80) were performed.…”

Section: Novel Metabolites Of Buprenorphinementioning

confidence: 99%

Novel Metabolites of Buprenorphine Detected in Human Liver Microsomes and Human Urine

Chang¹,

Moody²,

McCance‐Katz³

2005

Drug Metab Dispos

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ABSTRACT:The in vitro metabolism of buprenorphine was investigated to explore new metabolic pathways and identify the cytochromes P450 (P450s) responsible for the formation of these metabolites. The resulting metabolites were identified by liquid chromatography-electrospray ionization-tandem mass spectrometry. In addition to norbuprenorphine, two hydroxylated buprenorphine (M1 and M2) and three hydroxylated norbuprenorphine (M3, M4, and M5) metabolites were produced by human liver microsomes (HLMs), with hydroxylation occurring at the tert-butyl group (M1 and M3) and at unspecified site(s) on the ring moieties (M2, M4, and M5). Time course and other data suggest that buprenorphine is N-dealkylated to form norbuprenorphine, followed by hydroxylation to form M3; buprenorphine is hydroxylated to form M1 and M2, followed by N-dealkylation to form M3 and M4 or M5. The involvement of selected P450s was investigated using cDNA-expressed P450s coupled with scaling models, chemical inhibition, monoclonal antibody (MAb) analysis, and correlation studies. The major enzymes involved in buprenorphine elimination and norbuprenorphine and M1 formation were P450s 3A4, 3A5, 3A7, and 2C8, whereas 3A4, 3A5, and 3A7 produced M3 and M5. Based on MAb analysis and chemical inhibition, the contribution of 2C8 was higher in HLMs with higher 2C8 activity, whereas 3A4/5 played a more important role in HLMs with higher 3A4/5 activity. Examination of human urine from subjects taking buprenorphine showed the presence of M1 and M3; most of M1 was conjugated, whereas 60 to 70% of M3 was unconjugated.Buprenorphine, a semisynthetic derivative of the alkaloid thebaine (Lewis, 1973), is a partial -opioid agonist and -opioid antagonist (Cowan et al., 1977). It was first developed as an analgesic for moderate to severe pain in the early 1970s, but is currently more widely used as a replacement therapy for opiate dependence. Buprenorphine has comparable effects to methadone in regard to treatment of opiate-dependent patients (Strain et al., 1996;Johnson et al., 2000), but has reduced risk because of the "ceiling effect" associated with its partial -opioid agonist properties (Walsh et al., 1994(Walsh et al., , 1995.Absorption, distribution, metabolism, and excretion studies of buprenorphine have been carried out in humans using gas chromatography-mass spectrometry (Cone et al., 1984), and in animals using thin-layer chromatography of tritiated buprenorphine (Brewster et al., 1981;Pontani et al., 1985). These studies suggested that buprenorphine was mainly metabolized by N-dealkylation and glucuronidation of both buprenorphine and norbuprenorphine. A tentative 6-O-demethyl norbuprenorphine in free and conjugated form was observed in rat urine (Pontani et al., 1985), and some unknown polar metabolites were found in rat bile samples (Brewster et al., 1981). No evidence was given for additional metabolites in humans (Cone et al., 1984). However, a recent study by Picard et al. (2005) using liquid chromatography-tandem mass spectrometry identified the pres...

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“…In general, the production of all three metabolites increased with increases in buprenorphine concentration, but there were some cases in which no norbuprenorphine or norbuprenorphine-3-glucuronide was detected at either of the concentrations of buprenorphine used (data not shown). The primary cultures of human hepatocytes did not replicate the formation of norbuprenorphine seen in humans or HLM incubated with buprenorphine supplemented with a source of NADPH (Moody et al, 2002;Chang and Moody, 2005;Huang et al, 2006). The potential for the intestines to form norbuprenorphine was determined by comparing production of buprenorphine metabolites in HLM and HSIM.…”

Section: Resultsmentioning

confidence: 99%

“…LC-ESI-MS/MS was performed essentially as described by Huang et al (2006). For hepatocyte culture media, 0.25-ml aliquots were used; for microsomal incubates, the entire mixture along with the methanol used to terminate the reaction was used.…”

Section: Lc-esi-ms/ms Enantiomer-selective Determination Of R-and S-mmentioning

confidence: 99%

Effect of Rifampin and Nelfinavir on the Metabolism of Methadone and Buprenorphine in Primary Cultures of Human Hepatocytes

et al. 2009

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ABSTRACT:We tested the hypothesis that primary cultures of human hepatocytes could predict potential drug interactions with methadone and buprenorphine. Hepatocytes (five donors) were preincubated with dimethyl sulfoxide (DMSO) (vehicle), rifampin, or nelfinavir before incubation with methadone or buprenorphine. Culture media (0-60 min) was analyzed by liquid chromatography-tandem mass spectrometry for R-and S-methadone and R-and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) or for buprenorphine, norbuprenorphine, and their glucuronides [buprenorphine-3-glucuronide (B-3-G) and norbuprenorphine-3-glucuronide (N-3-G)]. R-and S-EDDP were detected in three of five, four of five, and five of five media from cells pretreated with DMSO, nelfinavir, and rifampin. R-EDDP increased 3.1-and 26.5-fold, and S-EDDP increased 2.5-and 21.3-fold after nelfinavir and rifampin. The rifampin effect was significant. B-3-G production was detected in media of all cells incubated with buprenorphine and accounted for most of the buprenorphine loss from culture media; it was not significantly affected by either pretreatment. Norbuprenorphine and N-3-G together were detected in three of five, four of five, and five of five donors pretreated with DMSO, nelfinavir and rifampin, and norbuprenorphine in one of five, one of five, and two of five donors. Although there was a trend for norbuprenorphine (2.8-and 4.9-fold) and N-3-G (1.7-and 1.9-fold) to increase after nelfinavir and rifampin, none of the changes were significant. To investigate low norbuprenorphine production, buprenorphine was incubated with human liver and small intestine microsomes fortified to support both N-dealkylation and glucuronidation; N-dealkylation predominated in small intestine and glucuronidation in liver microsomes. These studies support the hypothesis that methadone metabolism and its potential for drug interactions can be predicted with cultured human hepatocytes, but for buprenorphine the combined effects of hepatic and small intestinal metabolism are probably involved.

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The In Vivo Glucuronidation of Buprenorphine and Norbuprenorphine Determined by Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry

Cited by 71 publications

References 22 publications

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

Novel Metabolites of Buprenorphine Detected in Human Liver Microsomes and Human Urine

Effect of Rifampin and Nelfinavir on the Metabolism of Methadone and Buprenorphine in Primary Cultures of Human Hepatocytes

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