Formation of a quaternary N-glucuronide of amitriptyline in human liver microsomes.
Amitriptyline N-glucuronide was isolated from urine of a patient treated with therapeutic doses of amitriptyline. The glucuronide was hydrolyzed by hot alkaline treatment and, to a lesser degree, by treatment with beta-glucuronidase. A method for the direct measurement of amitriptyline glucuronide by HPLC was developed. Human liver microsomes were shown to glucuronidate amitriptyline in the presence of UDPGA, and the activity varied 7-fold among microsomes from 13 different human livers. The glucuronidation of amitriptyline was inhibited by p-nitrophenol but not by morphine. E-10-hydroxynortriptyline, a major metabolite of amitriptyline, had only a slight inhibitory effect on the glucuronidation of amitriptyline. No significant correlation was found between the glucuronidation of amitriptyline and that of E-10-hydroxynortriptyline in the microsomes studied.
Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Sweden.
M L
ML
Dahl-Puustinen
L
L
Bertilsson
D000639:Amitriptyline / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
D005965:Glucuronates; D000639:Amitriptyline