The Effect of Saquinavir on the Rate of Metabolism of Midazolam
Abstract
Midazolam (MDZ) is used extensively for sedation by clinicians including anesthesia providers. There have been reports that its effects have been enhanced in the presence of other drugs with negative patient outcomes. The P450 mixed function oxidase system contains an enzyme subfamily known as CYP3A. These enzymes have been identified as primarily responsible for the metabolism of MDZ. Protease inhibitors such as saquinavir may inhibit some P450 isoforms. The metabolism of MDZ in the presence of protease inhibitors is presently unclear. This study examines the effect of saquinavir on the rate of metabolism of MDZ. Human liver microsomes were incubated with MDZ with and without saquinavir. The ratio between MDZ's major metabolite alpha-hydroxy MDZ and the internal standard lorazepam were obtained using high performance liquid chromotography (HPLC). These ratios were then compared to those results in the presence of saquinavir. The incubation concentrations of MDZ were similar to therapeutic concentrations of (0.5 micronM, lmicronM, 3micronM, 6 micronM, l2 micronM) and saquinavir (0.0 micronM, 0.3 micronM, l.0 micronM, 3.0 micronM and l0.0 micronM). MDZ was inhibited 56.73% +/- 5.63. The Ki was determined to be 3.4 micronM. The interaction exhibited properties of mixed inhibition. These results showed that the rate of metabolism of MDZ was statistically significantly decreases in the presence of saquinavir (p<05).
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 03, 2000
- Accession Number
- ADA372317
Entities
People
- Brian G. Todd
Organizations
- Uniformed Services University of the Health Sciences