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Abstract
1. Triazolam (TRZ) has been used extensively in rat to evaluate its benzodiazepine agonist central nervous system effects. However, the pharmacokinetics of TRZ in the male rat are not well understood.
2. To characterize further TRZ biotransformation across species, the NADPH-dependent biotransformation of TRZ was examined in rat and human liver microsomes. The role of specific cytochrome P450s (CYPs) in the biotransformation of TRZ in the rat were also determined using both rat cDNA-expressed CYPs and chemical and antibody inhibition techniques.
3. The formation of TRZ's primary hydroxylated products, α-OH- and 4-OH-TRZ, was consistent with a single-enzyme Michaelis–Menten model in humans.
4. Although 4-OH-TRZ formation in the male rat liver was also approximated by a single-enzyme model, a second low-affinity component was identified as contributing to α-OH-TRZ formation in the rat.
5. The Km values for the primary metabolic pathway differed between the two species. However, the net intrinsic clearances were similar for the rat and human.
6. As observed previously for humans, chemical and antibody inhibition studies suggested that CYP3A enzymes contribute significantly to TRZ hydroxylation in the rat. This finding was further supported by the use of rat cDNA-expressed CYPs.
7. The male rat might serve as a useful model for evaluating mechanisms regulating TRZ metabolism in vivo.