Inhibition of acetaminophen and lorazepam glucuronidation <i>in vitro</i> by probenecid

Moltke, Lisa L. von; Manis, M; Harmatz, Jerold S.; Poorman, Roger A.; Greenblatt, David J.

doi:10.1002/bdd.2510140204

Cited by 25 publications

(24 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of studies have also shown that PRB inhibits the activity of UGTs [14–21]. We have previously reported the inhibitory effect of PRB on acetaminophen and lorazepam glucuronidation in vitro and in vivo [13,22]. In this study, we did not evaluate which specific isoforms are responsible for 2ME2 glucuronidation, nor did we determine the inhibitory effect of PRB vs individual UGT isoforms.…”

Section: Discussionmentioning

confidence: 93%

“…Glucuronidation via UDP‐glucuronyl transferases (UGTs)[9] is considered to be the principal pathway responsible for 2ME2 metabolism [10]. Probenecid (PRB), which is mainly used for gout treatment,[11,12] is also a known inhibitor of UGTs [13–22]. Therefore, we evaluated the inhibitory effect of PRB on 2ME2 glucuronidation using an in‐vitro model of human liver microsomes (HLMs).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of 2-methoxyestradiol glucuronidation by probenecid

Qian

Sherbini

Matin

et al. 2015

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Inhibition of 2-methoxyestradiol glucuronidation by probenecid

Qian

Sherbini

Matin

et al. 2015

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

show abstract

“…UGT activities using nine other marker substrates (estradiol, trifluoperazine, 4-nitrophenol, propofol, acetaminophen, azidothymidine, R-and S-oxazepam and morphine) were measured with the same set of human liver microsomes. Acetaminophen-UGT activity was assayed as described previously (von Moltke et al, 1993;Court and Greenblatt, 1997a). All other assays were similar to that described for serotonin-UGT with the following relevant differences.…”

Section: Methodsmentioning

confidence: 99%

Validation of Serotonin (5-Hydroxtryptamine) as an in Vitro Substrate Probe for Human UDP-Glucuronosyltransferase (UGT) 1A6

Krishnaswamy¹,

Duan²,

Moltke³

et al. 2003

Drug Metab Dispos

Self Cite

104

View full text Add to dashboard Cite

ABSTRACT:Investigation of human UDP-glucuronosyltransferase (UGT) isoforms has been limited by a lack of specific substrate probes. In this study serotonin was evaluated for use as a probe substrate for human UGT1A6 using recombinant human UGTs and tissue microsomes. Of the 10 commercially available recombinant UGT isoforms, only UGT1A6 catalyzed serotonin glucuronidation. Serotonin-UGT activity at 40 mM serotonin concentration varied more than 40-fold among human livers (n ‫؍‬ 54), ranging from 0.77 to 32.

show abstract

“…An in vitro UGT activity assay using oxazepam as substrate was developed based on methods previously used in this laboratory (von Moltke et al, 1993;Court and Greenblatt, 1997a,b). Incubations (250 l for HLMs, 100 l for expressed UGTs) were performed at 37°C in 50 mM phosphate buffer (pH 7.5) with 5 mM MgCl 2 , 5 mM UDPGA, and (R,S)-oxazepam (10 -1000 M).…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Conjugation of Oxazepam by Human UDP-Glucuronosyltransferases (UGTs): S-Oxazepam Is Glucuronidated by UGT2B15, While R-Oxazepam Is Glucuronidated by UGT2B7 and UGT1A9

Court

Duan²,

Guillemette³

et al. 2002

Drug Metab Dispos

Self Cite

156

121

View full text Add to dashboard Cite

ABSTRACT:(R,S)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that is metabolized primarily by hepatic glucuronidation. In previous studies, S-oxazepam (but not R-oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study was to identify UDP-glucuronosyltransferase (UGT) isoforms mediating R-and S-oxazepam glucuronidation in human liver, with the long term objective of elucidating the molecular genetic basis for this drug metabolism polymorphism. All available recombinant UGT isoforms were screened for R-and S-oxazepam glucuronidation activities. Enzyme kinetic parameters were then determined in representative human liver microsomes (HLMs) and in UGTs that showed significant activity. Oxazepam is a 1,4-benzodiazepine derivative that is used in clinical practice for its anxiolytic, sedative, and anticonvulsant effects (Greenblatt et al., 1980(Greenblatt et al., , 1981. In humans, this drug is cleared from the body almost exclusively by hepatic glucuronidation, followed by urinary excretion (Abernethy et al., 1983). Oxazepam is formulated as a racemic preparation of S-and R-stereoisomers although the S-enantiomer is thought to be much more active as a benzodiazepine receptor agonist compared with the R-enantiomer (Mohler et al., 1978). Conjugation occurs via the hydroxyl group attached to the asymmetric 3-carbon position yielding diastereomeric glucuronides that are readily separated by routine high pressure liquid chromatography (HPLC 1 ) (Mascher et al., 1984;Patel et al., 1995a).Interindividual variability in the pharmacokinetics and metabolism of (R,S)-oxazepam have been investigated in human volunteers (Patel et al., 1995a). S-Oxazepam glucuronide was found to be formed preferentially over R-oxazepam glucuronide with S/R glucuronide diastereomeric ratios in the plasma and urine of volunteers averaging 3.5 Ϯ 0.6 and 3.9 Ϯ 0.8, respectively. Interestingly, in 2 of 11 subjects (18%), the S/R ratio in the urine was relatively low (Ͻ1.9). Since the plasma clearance of oxazepam in these individuals was also very low (Ͻ0.6 ml/min/kg) compared with other individuals (0.9 -1.4 ml/min/ kg), it was concluded that these differences probably were the result of slower S-oxazepam clearance by glucuronidation in a significant minority of the study population (i.e., a "slow metabolizer" phenotype). Although pharmacodynamic measurements were not made, the relatively slow elimination of oxazepam would be expected to result in prolonged sedation in these individuals.In vitro studies using human liver microsomes (HLMs) showed a similar picture in that S-oxazepam glucuronide was the predominant metabolite (S/R ratios averaging 4.0), and 4 of 37 livers displayed relatively slow oxazepam glucuronidation activities coinciding with low S/R metabolite ratios (Ͻ2.0) (Patel et al., 1995a). Enzyme kinetic analysis showed that the low glucuronidation activity was associated with higher apparent K m values and lower V max values for S-oxazepam glucuronidation in the four atypical livers compared with ...

show abstract

Inhibition of acetaminophen and lorazepam glucuronidation in vitro by probenecid

Cited by 25 publications

References 20 publications

Inhibition of 2-methoxyestradiol glucuronidation by probenecid

Inhibition of 2-methoxyestradiol glucuronidation by probenecid

Validation of Serotonin (5-Hydroxtryptamine) as an in Vitro Substrate Probe for Human UDP-Glucuronosyltransferase (UGT) 1A6

Stereoselective Conjugation of Oxazepam by Human UDP-Glucuronosyltransferases (UGTs): S-Oxazepam Is Glucuronidated by UGT2B15, While R-Oxazepam Is Glucuronidated by UGT2B7 and UGT1A9

Contact Info

Product

Resources

About