Prolonged sedation due to accumulation of conjugated metabolites of midazolam

Bauer, Tilman; Ritz, R; Haberthür, Christoph; Haefeli, Walter E.; Scollo-Lavizzari, G; Ha, Huy Riêm; Hunkeler, Walter; Sleight, Andrew J.

doi:10.1016/s0140-6736(95)91209-6

Cited by 299 publications

(163 citation statements)

References 13 publications

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“…82), with the former possessing intrinsic binding activity to the benzodiazepine receptor similar to that of the parent drug (Richelson et al, 1991). Furthermore, the glucuronide conjugate of 19-hydroxymidazolam may also contribute to activity, based on the observation of prolonged activity in renal insufficiency patients who are less able to renally clear this metabolite (Bauer et al, 1995). Plasma protein binding of the glucuronide metabolite is considerably lower than midazolam; however, the ability of the glucuronide metabolite to penetrate the brain relative to the parent is unknown, thus precluding a true assessment of the relative contributions of parent and metabolite to effect.…”

Section: Drugs With Metabolites That Possess Target Potency But Comentioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

137

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Section: Drugs With Metabolites That Possess Target Potency But Comentioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

137

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“…However, the clinical importance of the 1-hydroxymidazolam as a sedative is limited because of the rapid glucuronidation and much shorter elimination half-life (0.8 h) compared with that of midazolam (Bornemann et al, 1985). Accumulation of conjugated 1-hydroxymidazolam has been reported to result in a clinically significant prolongation of the sedative effects of midazolam in patients with severe renal dysfunction (Bauer et al, 1995). The production of 4-hydroxymidazolam is insignificant, and this metabolite is clinically unimportant (Mandema et al, 1992).…”

Section: Pharmacokinetics and Biotransformation Of Commonly Used Bmentioning

confidence: 99%

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

et al. 2011

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“…In humans, urinary recovery of 1Ј-hydroxymidazolam glucuronide accounted for 60 to 70% of an administered dose of [ 14 C]midazolam (Heizmann and Ziegler, 1981). It has been reported that elevated serum levels of 1Ј-hydroxymidazolam glucuronide were found in patients with renal failure after administration of midazolam and may account for the prolonged sedation observed in those patients (Bauer et al, 1995;Hirata et al, 2003).…”

mentioning

confidence: 99%

Characterization of 1′-Hydroxymidazolam Glucuronidation in Human Liver Microsomes

Zhu¹,

Bush²,

Doss³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Midazolam is a potent benzodiazepine derivative with sedative, hypnotic, anticonvulsant, muscle-relaxant, and anxiolytic activities. It undergoes oxidative metabolism catalyzed almost exclusively by the CYP3A subfamily to a major metabolite, 1-hydroxymidazolam, which is equipotent to midazolam. 1-Hydroxymidazolam is subject to glucuronidation followed by renal excretion. To date, the glucuronidation of 1-hydroxymidazolam has not been evaluated in detail. In the current study, we identified an unreported quaternary N-glucuronide, as well as the known O-glucuronide, from incubations of 1-hydroxymidazolam in human liver microsomes enriched with uridine 5-diphosphoglucuronic acid (UDPGA). The structure of the Nglucuronide was confirmed by nuclear magnetic resonance analysis, which showed that glucuronidation had occurred at N-2 (the imidazole nitrogen that is not a part of the benzodiazepine ring). In a separate study, in which midazolam was used as the substrate, an analogous N-glucuronide also was detected from incubations with human liver microsomes in the presence of UDPGA. Investigation of the kinetics of 1-hydroxymidazolam glucuronidation in human liver microsomes indicated autoactivation kinetics (Hill coefficient, n ‫؍‬ 1.2-1.5). The apparent S 50 values for the formation of O-and N-glucuronides were 43 and 18 M, respectively, and the corresponding apparent V max values were 363 and 21 pmol/mg of microsomal protein/min. Incubations with recombinant human uridine diphosphate glucuronosyltransferases (UGTs) indicated that the O-glucuronidation was catalyzed by UGT2B4 and UGT2B7, whereas the N-glucuronidation was catalyzed by UGT1A4. Consistent with these observations, hecogenin, a selective inhibitor of UGT1A4, selectively inhibited the N-glucuronidation, whereas diclofenac, a potent inhibitor of UGT2B7, had a greater inhibitory effect on the O-glucuronidation than on the N-glucuronidation. In summary, our study provides the first demonstration of N-glucuronidation of 1-hydroxymidazolam in human liver microsomes.

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Prolonged sedation due to accumulation of conjugated metabolites of midazolam

Cited by 299 publications

References 13 publications

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

Characterization of 1′-Hydroxymidazolam Glucuronidation in Human Liver Microsomes

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