Related Experiment Videos
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.
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.
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.