In vitro interaction of clopidogrel and its hydrolysate with OCT1, OCT2 and OAT1.

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Li L, Song F, Tu M, Wang K, Zhao L, Wu X, Zhou H, Xia Z, Jiang H

In vitro interaction of clopidogrel and its hydrolysate with OCT1, OCT2 and OAT1.

Int J Pharm. 2014 Apr 25;465(1-2):5-10. doi: 10.1016/j.ijpharm.2014.02.003. Epub 2014 Feb 11.

PubMed ID

24530383 [ View in PubMed

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Abstract

Clopidogrel (CP) is metabolized by CYPs to the active metabolite, or hydrolyzed by esterase to clopidogrel carboxylate (CPC) in liver, and CPC is partly excreted from urine. Therefore, the objective of the present study was to evaluate the interactions of CP and CPC with organic cation transporter 1 (OCT1) (in liver), and CPC with organic cation transporter 2 (OCT2) and organic anion transporter 1 (OAT1) (in kidney). Both CP and CPC inhibited the uptake of 1-methyl-4-phenylpyridinium (MPP(+)) and metformin, typical substrates of OCT1, in MDCK-hOCT1 cells with low IC(5)(0) (0.307-14.0 muM). CPC (100 muM) reduced the uptake of MPP(+) and metformin mediated by OCT2 in MDCK-hOCT2 cells to 60.8% and 33.6% of the control, CPC (500 muM) decreased the uptake of 6-carboxyfluorescein (6-CFL) and para-aminohippuric acid (PAH), substrates of OAT1, in MDCK-hOAT1 cells to 64.6% and 79.4% of the control. CP and CPC were also found to inhibit other drugs of OCT1 substrates, such as lamivudine and amantadine, in MDCK-hOCT1 cells with the IC(5)(0) of 1.97-4.15muM, except CPC on amantadine (IC(5)(0)>100 muM). The inhibition of CP and CPC on lamivudine uptake in primary rat hepatocytes was also confirmed with the IC(5)(0) of 2.91 and 1.25muM, respectively. Additionally, CP and CPC were not substrates of OCT1 and OCT2, whereas CPC was a substrate of OAT1 with the Km of 5.61 muM. In conclusion, CP and CPC are strong inhibitors of OCT1, but weak inhibitors of OCT2 and OAT1, and CPC is a high affinity substrate of OAT1.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Amantadine	Solute carrier family 22 member 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Clopidogrel	Solute carrier family 22 member 1	Protein	Humans	No	Inhibitor	Details
Clopidogrel	Solute carrier family 22 member 2	Protein	Humans	No	Inhibitor	Details