4.7 Article

Pharmacokinetics, mass balance, and metabolism of [14C]vicagrel, a novel irreversible P2Y12 inhibitor in humans

Journal

ACTA PHARMACOLOGICA SINICA
Volume 42, Issue 9, Pages 1535-1546

Publisher

NATURE PUBL GROUP
DOI: 10.1038/s41401-020-00547-7

Keywords

vicagrel; [C-14]vicagrel; vicagrel pharmacokinetics; vicagrel metabolism; mass balance; P2Y(12) receptor inhibitor

Funding

  1. Jiangsu Vcare PharmaTech Co., Ltd.
  2. National Natural Science Foundation of China [81903701]
  3. National Key New Drug Creation Special Programs [2017ZX09304-021]
  4. Suzhou Key Laboratory of Drug Clinical Research and Personalized Medicine [SZS201719]
  5. Special Research Fund of Wu Jieping Medical Foundation of Clinical Pharmacy Branch of Chinese Medical Association [320.6750.19090-50]

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Vicagrel, a novel irreversible P2Y(12) receptor inhibitor, is being studied in phase III trials for acute coronary syndromes in China. This study found that vicagrel is rapidly absorbed, with metabolism primarily occurring on the thiophene ring, and renal elimination plays a crucial role in its disposition.
Vicagrel, a novel irreversible P2Y(12) receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [C-14]vicagrel (120 mu Ci). Vicagrel absorption was fast (T-max = 0.625 h), and the mean t(1/2) of vicagrel-related components was similar to 38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUC(inf) ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC(0-8 h) plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.

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