Influence of organic anion transporter 1/3 on the pharmacokinetics and renal excretion of ginkgolides and bilobalide.
Animals
Biological Transport
Cyclopentanes
/ blood
Dogs
Furans
/ blood
Ginkgolides
/ blood
HEK293 Cells
Humans
Kidney
/ metabolism
Madin Darby Canine Kidney Cells
Male
Organic Anion Transport Protein 1
/ genetics
Organic Anion Transporters, Sodium-Independent
/ genetics
Rats
Renal Elimination
Tissue Distribution
Bilobalide
Ginkgolides
Herb-drug interaction
Organic anion transporter
Pharmacokinetics
Probenecid
Journal
Journal of ethnopharmacology
ISSN: 1872-7573
Titre abrégé: J Ethnopharmacol
Pays: Ireland
ID NLM: 7903310
Informations de publication
Date de publication:
28 Oct 2019
28 Oct 2019
Historique:
received:
23
04
2019
revised:
09
07
2019
accepted:
16
07
2019
pubmed:
22
7
2019
medline:
6
2
2020
entrez:
21
7
2019
Statut:
ppublish
Résumé
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. 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. Uptake of ginkgolide A, B, C and bilobalide in Madin-Darby Canine Kidney (MDCK) 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. 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 probenecid-treated rats compared to control rats (893.48 vs. 1123.85, 314.91 vs. 505.74, and 2724.97 vs. 3096.40 μg/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. 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.
Identifiants
pubmed: 31325605
pii: S0378-8741(19)31576-4
doi: 10.1016/j.jep.2019.112098
pii:
doi:
Substances chimiques
Cyclopentanes
0
Furans
0
Ginkgolides
0
Organic Anion Transport Protein 1
0
Organic Anion Transporters, Sodium-Independent
0
organic anion transport protein 3
0
bilobalide
M81D2O8H7U
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112098Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.