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Pharmacokinetics of midazolam and metabolites in a patient with refractory status epilepticus treated with extraordinary doses of midazolam

Bodmer, M. and Link, B. and Grignaschi, N. and Kummer, O. and Ruegg, S. and Haschke, M. and Krähenbühl, S.. (2008) Pharmacokinetics of midazolam and metabolites in a patient with refractory status epilepticus treated with extraordinary doses of midazolam. Therapeutic drug monitoringNew York : Raven Press, Vol. 30, H. 1. pp. 120-124.

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Official URL: http://edoc.unibas.ch/dok/A6002830

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Abstract

The authors present a patient with refractory epilepsy who was treated with very high doses (up to 4 mg/min) of intravenous midazolam, phenytoin, carbamazepine, and other antiepileptics. Because it was known from the literature that the half-life of midazolam can increase at high dosage, the kinetics of midazolam (MDZ), 1'-hydroxymidazolam, and 4-hydroxymidazolam were assessed at steady state (dosage 1 mg/min) and after stopping treatment. Total body clearance of MDZ (33 L/kg) and intrinsic hepatic clearance (19 mL/min/kg) at steady state were both five to 10 times higher than after normal therapeutic doses, demonstrating hepatic cytochrome (CYP) 3A induction. Despite the high body clearance, the half-life of MDZ was in the range of 24 hours, approximately 10 times higher than after normal therapeutic doses. The volume of distribution at steady state was 33 L/kg, approximately 50 times higher than after normal therapeutic doses. The free fraction of MDZ was 58% at steady state, much higher than the 3% to 6% at normal therapeutic doses. The kinetics of intravenous MDZ is strongly dependent on its dose and on hepatic CYP3A activity. Even in patients with hepatic CYP3A induction, the half-life of MDZ increases with high doses as a result of a rise in its volume of distribution, which is a consequence of an increase in the free fraction of MDZ.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Neurologie
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Neurologie
03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
UniBasel Contributors:Krähenbühl, Stephan and Rüegg, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
ISSN:0163-4356
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:25 Apr 2014 08:01
Deposited On:25 Apr 2014 08:01

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