RT Journal Article SR Electronic T1 Biphasic Kinetics of Quaternary Ammonium Glucuronide Formation from Amitriptyline and Diphenhydramine in Human Liver Microsomes JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 340 OP 345 VO 25 IS 3 A1 Breyer-Pfaff, Ursula A1 Fischer, Dorothee A1 Winne, Dietrich YR 1997 UL http://dmd.aspetjournals.org/content/25/3/340.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics