tolterodine-tartrate and Chemical-and-Drug-Induced-Liver-Injury

To determine efficacy of the analgesic flupirtine in the treatment of overactive bladder syndrome in a proof-of-concept study.. Double-blind, double-dummy, three-armed comparison of flupirtine extended release (400 mg/day, titrated to 600 mg/day), tolterodine extended release (4 mg/day) and placebo for 12 weeks.. When major elevations of liver enzymes (more than three times the upper normal limit) were detected in several flupirtine-exposed patients, the study was prematurely discontinued. Based on study-end data, hepatotoxicity was detected in 31% of patients receiving flupirtine for ≥ 6 weeks.. Unexpected frequent and relevant toxicity can occur when testing an established drug for a new indication.

Topics: Aged; Aminopyridines; Analgesics; Benzhydryl Compounds; Chemical and Drug Induced Liver Injury; Cresols; Double-Blind Method; Female; Humans; Liver; Male; Middle Aged; Muscarinic Antagonists; Phenylpropanolamine; Syndrome; Tolterodine Tartrate; Urinary Bladder, Overactive

Tolterodine (TOL) is an antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency, and urge incontinence. During the clinical use of TOL, adverse events such as liver injury took place. The present study aimed at the investigation of the metabolic activation of TOL possibly associated with its hepatotoxicity. One GSH conjugate, two NAC conjugates, and two cysteine conjugates were found in both mouse and human liver microsomal incubations supplemented with TOL, GSH/NAC/cysteine, and NADPH. The detected conjugates suggest the production of a quinone methide intermediate. The same GSH conjugate was also observed in mouse primary hepatocytes and in the bile of rats receiving TOL. One of the urinary NAC conjugates was observed in rats administered TOL. One of the cysteine conjugates was found in a digestion mixture containing hepatic proteins from animals administered TOL. The observed protein modification was dose-dependent. CYP3A primarily catalyzes the metabolic activation of TOL. Ketoconazole (KTC) pretreatment reduced the generation of the GSH conjugate in mouse liver and cultured primary hepatocytes after TOL treatment. In addition, KTC reduced the susceptibility of primary hepatocytes to TOL cytotoxicity. The quinone methide metabolite may be involved in TOL-induced hepatotoxicity and cytotoxicity.

Topics: Activation, Metabolic; Animals; Chemical and Drug Induced Liver Injury; Cysteine; Cytochrome P-450 CYP3A; Glutathione; Humans; Ketoconazole; Mice; Microsomes, Liver; Rats; Tolterodine Tartrate