Glucuronidation of Amitriptyline in Man in Vivo

Abstract

The urinary excretion of amitriptyline (AT) as N-glucuronide was studied in healthy volunteers after single oral doses of AT and in patients on continuous treatment with AT. In the volunteers, 8 +/- 3% of a 25 mg dose of AT was recovered in urine as glucuronide during 108 hr. No difference between slow and rapid debrisoquine hydroxylators with respect to the excretion of AT glucuronide was seen. 0.08 to 1.68% of the given AT dose was recovered in urine in unchanged form. The excretion of unchanged AT correlated with the debrisoquine metabolic ratio (rs = 0.61; p less than 0.01). In 5 patients on continuous treatment with AT (125-150 mg/day), 8 +/- 5% of the daily dose was recovered in 24-hr urine as AT glucuronide. The present study shows that direct glucuronidation is a minor metabolic pathway of AT in man in vivo both after single low doses and during continuous treatment with therapeutic doses.

N+-Glucuronidation of aliphatic tertiary amines in human: antidepressant versus antipsychotic drugs

“…For three other tricyclic antidepressant drugs, amitriptyline, dothiepin and doxepin, a N+ -glucuronide metabolite has been identified in human urine (Lehman et a/. 1983, Kawahara et al 1986, Dahl-Puustinen and Bertilsson 1987, Dahl-Puustinen et al 1989, Breyer-Pfaff et al 1990, Luo et al 1991a, Becher et al 1992. Cyclobenzaprine, a muscle-relaxant that is structurally related to these latter three drugs (16; figure l), also forms such a metabolite in man (Hucker et al 1978).…”

“…Since in the latter cases the mean urinary excretion of the respective N' -glucuronide metabolites has been found to be in the range 8-22% of the oral dose administered (Hucker et al 1978, Kawahara et al 1986, Dahl-Puustinen et al 1989, Breyer-Pfaff et al 1990, Luo et al 1991a, Becher et al 1992, it is apparent that N+-glucuronidation is far more extensive for tricyclic antidepressants and related drugs that possess a 5H-dibenzo[a,dlcyclohepten-5-ylidene or related ring system (amitriptyline, cyclobenzaprine, dothiepin, doxepin) than a SH-dibenz[b,f]azepine ring system (clomipramine, imipramine, trimipramine). Finally, of the drugs examined, the mean urinary excretion of the respective N + -glucuronide metabolite was greatest for the antipsychotic drugs clozapine and loxapine.…”

“…However, only in the case of one antipsychotic drug, namely chlorpromazine (Chaudhary et al 1988) and five antidepressant drugs, namely amitriptyline (Lehman et al 1983, Dahl-Puustinen and Bertilsson 1987, Dahl-Puustinen et al 1989 al. 1990al.…”

In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

“…The metabolism of phenobarbitone involves glucosidation, glucuronidation [37] and CYP2C19-mediated oxidation [38], but the contributions of other CYP isoforms are not known. CYP2C19, CYP2D6 and CYP3A4 seem to be the major enzymes mediating the metabolism of amitriptyline, but CYP2C9 is also involved [39] and a small fraction of the dose is eliminated via direct glucuronidation [40]. Consequently, the inhibitory effects of valproic acid on CYP2C9 and UDP-glucuronyltransferases [37,41] probably explain the valproic acid-phenobarbitone [4±7] and valproic acid±amitriptyline interactions [10].…”