title: Pharmacokinetics of midazolam and metabolites in a patient with refractory status epilepticus treated with extraordinary doses of midazolam.
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.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Bodmer
authors.forename: Bettina
authors.initials: B
authors.lastname: Link
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grignaschi
authors.forename: Oliver
authors.initials: O
authors.lastname: Kummer
authors.forename: Stephan
authors.initials: S
authors.lastname: Ruegg
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D006801:Humans; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D010672:Phenytoin / Q000008:administration & dosage; D013226:Status Epilepticus / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D010672:Phenytoin; D008874:Midazolam