Influence of organic anion transporter 1/3 on the pharmacokinetics and renal excretion of ginkgolides and bilobalide

Ethnopharmacological relevance: The major terpene lactones of ginkgo biloba extract (GBE) include ginkgolide A, B, C and bilobalide are used for the protection of cardiovascular, cerebrovascular and neurodegenerative diseases. Terpene lactones are orally bioavailable and predominantly eliminated via the renal pathway. However, information on the transporters involved in the pharmacokinetics (PK) and renal excretion of terpene lactones is limited. Aim of the study: The objective of this study is to assess the role of OAT1/3 which are important transporters in the human kidney in the PK and renal excretion ginkgolide A, B, C and bilobalide. Materials and methods: Uptake of ginkgolide A, B, C and bilobalide in Madin-Darby Canine Kidney (MOCK) and human embryonic kidney 293 (HEK293) cells overexpressing OAT1 or OAT3, respectively were studied. To verify the result from in vitro cell models, the studies on PK, kidney accumulation and urinary excretion of ginkgolide A, B, C and bilobalide were carried out in rats. Results: The result showed that ginkgolide A, B, C and bilobalide are low-affinity substrates of OAT1/3. Following co-administration with probenecid, a typical inhibitor of OAT1/3, the rat plasma concentrations of ginkgolide A, B, C and bilobalide increased significantly. AUC showed a significant increase in the probenecidtreated rats compared to control rats (893.48 vs. 1123.85, 314.91 vs. 505.74, and 2724.97 vs. 3096.40 mu g/L*h for ginkgolide A, B and bilobalide, respectively), while the clearance of these compounds significantly decreased. The accumulation of ginkgolide A, B and bilobalide in the kidney of the probenecid-treated rats was reduced by 1.8, 2.4, and 1.5-fold, respectively; further reducing the cumulative urinary recovery of these compounds. Conclusion: The findings indicated that ginkgolide A, B and bilobalide are excreted via OAT1/3-mediated transport in the kidney and OAT1/3 inhibitor significantly influence the PK ginkgolides and bilobalide.