title: Increased volume of distribution prolongs midazolam half-life.
abstract: It has recently been shown by several investigators that the half-life (t1/2) of midazolam is prolonged (greater than 7 h) in a small proportion of the population. One group has inferred that this subpopulation represents a group of slow metabolizers of midazolam to alpha-OH-midazolam. Others disagree and postulate that there is an increase in the volume of distribution (V) resulting in a prolonged t1/2. This controversy led us to report experience from 90 subjects and patients where t1/2, V, and clearance (CL) were determined by both model-dependent and -independent pharmacokinetic analysis. We found a 5.6% (5 of 90) incidence of prolonged t1/2, similar to that previously reported. V was clearly increased without a decrease in CL in the five subjects with prolonged t1/2. Thus, the prolonged t1/2 is secondary to an increase in V and not a result of alterations in CL and metabolism.
authors.affiliation: Department of Drug Metabolism, Hoffmann-La Roche Inc., Nutley, NJ 07110.
authors.forename: R J
authors.initials: RJ
authors.lastname: Wills
authors.forename: K C
authors.initials: KC
authors.lastname: Khoo
authors.forename: P P
authors.initials: PP
authors.lastname: Soni
authors.forename: I H
authors.initials: IH
authors.lastname: Patel
mesh_terms: D000328:Adult; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D011863:Radioimmunoassay
chemical_list: D008874:Midazolam