Role of CYP3A enzymes in the biotransformation of triazolam in rat liver

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
J S WarringtonL L von Moltke

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, alpha-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 alpha-OH-TRZ formation in the rat. 5. The K(m) 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 wa...Continue Reading

References

Apr 1, 1990·Archives of Biochemistry and Biophysics·S ImaokaY Funae
Sep 1, 1996·Journal of Pharmaceutical Sciences·J GaudreaultG M Pollack
Mar 5, 1999·Journal of Psychopharmacology·G GriebelD J Sanger
Feb 28, 2001·Journal of Clinical Pharmacology·L L von MoltkeR I Shader
Jul 19, 2001·Journal of Neural Transmission·S M AburawiA S Attia
May 23, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jill S WarringtonDavid J Greenblatt
Aug 17, 2002·The Journal of Pharmacology and Experimental Therapeutics·Tsutomu KotegawaDavid J Greenblatt

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Citations

Jun 15, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Shweta PadmanabhanVinay K Holenarsipur
Oct 28, 2019·PloS One·Yufu WangChaoxi Luo

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