Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [¹⁴C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase

Abstract

HR011303, a promising selective URAT1 inhibitor, is currently being studied in a phase Ⅲ clinical trial in China for the treatment of hyperuricemia and gout. In the current study, the pharmacokinetics, mass balance, and metabolism of HR011303 were examined in six healthy Chinese male subjects who received a single oral dose of 10 mg of [ 14 C]HR011303 (80 µCi).The results showed that HR011303 was rapidly absorbed with a median T max = 1.50 h postdose, and the arithmetic mean t 1/2 of total radioactivity was approximately 24.2 h in plasma.The mean blood-to-plasma radioactivity concentration ratio was 0.66, suggesting the preferential distribution of drug-related components in plasma. At 216 h post-dose, the mean cumulative excreted radioactivity was 91.75% of the dose, including 81.50% in urine and 10.26% in feces. Six metabolites were identified, and the parent drug HR011303 was the most abundant component in plasma and feces, but a minor component in urine.Glucuronidation of the carboxylic acid moiety of HR011303 was the primary metabolic pathway in humans, amounting to 69.63% of the dose (M5, 51.57% of the dose; M5/2, 18.06% of the dose) in the urine; however, it was not detected in plasma. UGT2B7 was responsible for the formation of M5. Overall, after a single oral dose of 10 mg of [ 14 C]HR011303 (80 µCi), HR011303 and its main metabolites were eliminated via renal excretion. The major metabolic pathway was carboxylic acid glucuronidation, which was catalyzed predominantly by UGT2B7.