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Increased volume of distribution prolongs midazolam half-life

R J Wills1, K C Khoo, P P Soni

  • 1Department of Drug Metabolism, Hoffmann-La Roche Inc., Nutley, NJ 07110.

British Journal of Clinical Pharmacology
|February 1, 1990
PubMed

Insights

A small percentage of people experience a prolonged midazolam half-life (t1/2). This is due to an increased volume of distribution (V), not altered clearance (CL) or metabolism.

Area of Science:

  • Pharmacokinetics
  • Drug Metabolism
  • Clinical Pharmacology

Background:

  • A subset of the population exhibits an extended midazolam half-life (t1/2 > 7 hours).
  • This prolonged t1/2 has been attributed to either impaired metabolism or an increased volume of distribution (V).

Purpose of the Study:

  • To investigate the pharmacokinetic basis for the prolonged midazolam t1/2 in a subpopulation.
  • To differentiate between altered metabolism and changes in volume of distribution as the cause.

Main Methods:

  • Pharmacokinetic analysis (model-dependent and independent) of midazolam in 90 subjects and patients.
  • Determination of half-life (t1/2), volume of distribution (V), and clearance (CL).

Main Results:

  • A 5.6% incidence (5 of 90 subjects) of prolonged midazolam t1/2 was observed.
  • In subjects with prolonged t1/2, the volume of distribution (V) was significantly increased.
  • Clearance (CL) and metabolism were not decreased in these subjects.

Conclusions:

  • The prolonged midazolam half-life in this subpopulation is primarily caused by an increased volume of distribution (V).
  • Altered hepatic metabolism or reduced clearance (CL) is not the underlying mechanism for the extended t1/2.

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