2010
DOI: 10.1124/dmd.110.035295
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Metabolism of 1′- and 4-Hydroxymidazolam by Glucuronide Conjugation Is Largely Mediated by UDP-Glucuronosyltransferases 1A4, 2B4, and 2B7

Abstract: ABSTRACT:Midazolam undergoes oxidative hydroxylation by CYP3A to its metabolites, which are excreted mainly as glucuronidated conjugates into the urine. In this study, we examined the glucuronidation of hydroxymidazolam in human liver microsomes (HLMs) and characterized the UDP-glucuronosyltransferases (UGTs) involved in 1-and 4-hydroxymidazolam glucuronidation.Among the 12 UGT isoforms tested, the O-and N-glucuronidation of 1-hydroxymidazolam was mediated by UGT2B4/2B7 and 1A4, respectively. In contrast, the … Show more

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Cited by 66 publications
(55 citation statements)
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“…As reported, erlotinib and panaxytriol, an active component in Shenmai injection (Zeng et al, 2013), both showed significant activation on MDZ 19-hydroxylation, whereas the activation but not inhibition made it difficult for the in vivo extrapolation. Moreover, either glucuronidation of hydroxylmidazolam or direct glucuronidation of MDZ occurs in vitro and in vivo (Klieber et al, 2008;Hyland et al, 2009;Seo et al, 2010). The multiple metabolic pathways may partly compensate for the decrease in MDZ metabolic clearance caused by the addition of the inhibitor and would also make it difficult for the in vivo quantification.…”
Section: Discussionmentioning
confidence: 99%
“…As reported, erlotinib and panaxytriol, an active component in Shenmai injection (Zeng et al, 2013), both showed significant activation on MDZ 19-hydroxylation, whereas the activation but not inhibition made it difficult for the in vivo extrapolation. Moreover, either glucuronidation of hydroxylmidazolam or direct glucuronidation of MDZ occurs in vitro and in vivo (Klieber et al, 2008;Hyland et al, 2009;Seo et al, 2010). The multiple metabolic pathways may partly compensate for the decrease in MDZ metabolic clearance caused by the addition of the inhibitor and would also make it difficult for the in vivo quantification.…”
Section: Discussionmentioning
confidence: 99%
“…For this purpose it is particularly well suited because it is almost exclusively metabolized by CYP3A to 1'-OH-midazolam [6]. In the subsequent UDP-glucuronosyltransferase (UGT)-mediated phase II-reaction the main urinary metabolite 1'-OH-midazolam-glucuronide is formed [7]; 63-80% of the dose is found conjugated in the urine within 24 h, while only 1% is excreted unchanged [8]. The most predictive and reliable parameter for in vivo CYP3A activity is the metabolic clearance (CLmet) to 1'-OH-midazolam [9].…”
Section: Introductionmentioning
confidence: 99%
“…Because commercial standards for 20-HETE glucuronide are not available, quantifi cation of the glucuronide form of 20-HETE was accomplished using standard curves of 20-HETE. The glucuronidation of 20-HETE was compared with diclofenac glucuronidation among 44 HLMs of Koreans, as described previously ( 23,25 ). Briefl y, diclofenac (50 M) was incubated with pooled HLMs in 0.5 M Tris-HCl buffered mixture (pH 7.4) containing 1.5 mg/ml alamethicin.…”
Section: Assays Of 20-hete Glucuronidation Using Hlms and Recombinantmentioning
confidence: 99%
“…For in vitro 20-HETE glucuronidation assays, pooled HLMs or recombinant UGT was reconstituted in a reaction mixture containing 20 M 20-HETE and 1.5 mg/ml alamethicin in 0.5 M Tris-HCl buffer (pH 7.4), which was preincubated on ice for 15 min, as described previously ( 23 ). Because there is limited information on kinetics for 20-HETE glucuronidation by a set of UGT enzymes, 20 M 20-HETE was determined empirically for initial screening for UGT enzymes responsible for 20-HETE glucuronidation.…”
Section: Assays Of 20-hete Glucuronidation Using Hlms and Recombinantmentioning
confidence: 99%