Abstract
The tricyclic antidepressant amitriptyline and the H1-receptor antagonist diphenhydramine are conjugated in human liver microsomes fortified with UDP-glucuronic acid at their tertiary amino groups with the formation of quaternary ammonium glucuronides. The kinetics of the reactions were found to be biphasic with apparentKM1 andKM2 values of 1.4 μM and 311 μM for amitriptyline and 2.6 μM and 1180 μM for diphenhydramine in four liver samples.Vmax1 values varied between 2 and 17 pmol·mg protein−1·min−1for the two substrates and Vmax2 values between 80 and 740 pmol·mg protein−1·min−1. A close correlation existed between amitriptyline and diphenhydramine glucuronidation rates in microsomes from seven livers at concentrations corresponding to 10–40% ofKM2. At low concentrations, diphenhydramine competitively inhibited the glucuronidation of amitriptyline.Vmax/KMvalues of the high-affinity UDP-glucuronosyltransferase(s) (UGTs) exceed those of the low-affinity enzyme(s) severalfold, such that the former should make the major contribution toN-glucuronidation of the drugs at therapeutic concentrations in vivo.
Footnotes
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Send reprint requests to: Dr. Ursula Breyer-Pfaff, Department of Toxicology, University of Tübingen,Wilhelmstrasse 56, D-72074 Tübingen, Germany.
- Abbreviations used are::
- HL
- human liver
- UGT
- UDP-glucuronosyltransferase
- Received August 2, 1996.
- Accepted November 25, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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