The pharmacokinetics and conversion of the lactone to the carboxylate forms of ginkgolide B in rat plasma

Abstract

Ginkgolide B consists of three lactone groups, which may undergo hydrolysis, and lead to the rings opening in aqueous solution with different pHs. From mechanisms of pharmacological activity in vivo, the lactone appears to be the active form of the drug. Pharmacokinetics of lactone form (GB-lac) and the total of the lactone and carboxylate form (GB-tot) of ginkgolide B were investigated after intravenous administration of a dose of 4 mg/kg ginkgolide B. The rate of lactone hydrolysis was also studied in plasma in vitro. After intravenous administration, ginkgolide B in the original form was converted to its carboxylate form under simulated physiological conditions. The AUC_0 − ∞ of GB-lac constituted 63.5 ± 17.4% of the AUC_0 − ∞ of GB-tot. The ratio of average cumulation of excretion of lactone to carboxylate reached approximately 1 to 1 in urine. From the equilibrium of lactone hydrolysis in rat plasma in vitro, the k _obs was − 0.0176 min^− 1 and t _1/2 was 39.38 min. In conclusion, the equilibrium existed between lactone of ginkgolide B and its carboxylate form in vivo at physiological pH, which suggested that more attention should be focused on the original and the ionization forms of ginkgolide B and the conversion of the lactone into carboxylate in vivo.

Keywords:

• ginkgolide B
• pharmacokinetics
• lactone
• carboxylate
• conversion

Acknowledgements

This study was financially supported by National Natural Science Foundation of China (No. 81001592), the Key Project of Chinese Ministry of Education (No. 210101), the Key Project of Anhui University Provincial Natural Science Research Foundation (Nos. KJ2010A210, KJ2012A186) and Science and Technology Major Projects of Major New Drug Development of China (No. 2009ZX09103-399).