Novel dual GIP and GLP-1 receptor agonist, tirzepatide (TZP), is being developed as a potential weekly treatment for type 2 diabetes (T2DM), weight management and nonalcoholic steatohepatitis. The absorption, metabolism and excretion of a single subcutaneous (SC) dose of 14C-tirzepatide was investigated in Sprague Dawley rat and cynomolgus monkey. In addition, tissue distribution of 14C-tirzepatide was assessed in quantitative whole-body autoradiography (QWBA) study in pigmented Long Evans rat following a single SC dose.

14C-Tirzepatide was prepared by incorporating four 14C’s in the mini-PEG linker between the peptide backbone and the di-acid chain to provide a specific activity of ∼ 40 µCi/mg. Following a single SC dose of 14C-tirzepatide in rat (3 mg/kg) and monkey (0.5 mg/kg), total radioactivity recovery was > 97% over the course of study (336 hours for rat and 672 hours for monkey). The dosed radioactivity was similarly excreted via urine and feces in rats and monkeys. Metabolism of 14C-tirzepatide was characterized in plasma and excreta. Parent drug was the major component in circulation accounting for approximately 87% of total radioactivity in rat and 84% in monkey. Tirzepatide was primarily metabolized via catabolism of the peptide backbone and β-oxidation of the di-acid chain.

Following a single SC dose of 14C-tirzepatide in rats (3 mg/kg), radioactivity was distributed to tissues as early as the first collection time point at 1-hour post dose. The tissues with the highest radioactivity concentrations were observed in the dose site, kidney, cecum, urinary bladder, intervertebral ligaments, arterial wall, lungs, and liver, generally at 12 to 48 hours post dose.


J. Martin: Employee; Self; Eli Lilly and Company. K. Cassidy: Employee; Self; Eli Lilly and Company. B. Czeskis: None. J. Alberts: Employee; Self; Eli Lilly and Company. Y. Lao: Employee; Spouse/Partner; Eli Lilly and Company. J. Gluff: None. A.M. Niedenthal: None.

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