Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A.

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Shitara Y, Itoh T, Sato H, Li AP, Sugiyama Y

Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A.

J Pharmacol Exp Ther. 2003 Feb;304(2):610-6.

PubMed ID

12538813 [ View in PubMed

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Abstract

The mechanism involved in the clinically relevant drug-drug interaction (DDI) between cerivastatin (CER) and cyclosporin A (CsA) has not yet been clarified. In the present study, we examined the possible roles of transporter-mediated hepatic uptake in this DDI. The uptake of [(14)C]CER into human hepatocytes prepared from three different donors was examined. Kinetic analyses revealed K(m) values for the uptake of [(14)C]CER within the range of 3 to 18 microM, suggesting that more than 70% of the total uptake at therapeutic CER concentrations was accounted for by a saturable process, i.e., transporter-mediated uptake. This uptake was inhibited by CsA with K(i) values of 0.3 to 0.7 microM. The uptake of [(14)C]CER was also examined in human organic anion transporting polypeptide-2 (OATP2)-expressing Madin-Darby canine kidney cells (MDCKII). Saturable OATP2-mediated uptake of [(14)C]CER was observed and was also inhibited by CsA, with a K(i) value of 0.2 microM. These results suggest that the DDI between CER and CsA involves the inhibition of transporter-mediated uptake of CER and, at least in part, its OATP2-mediated uptake. The effect of CsA on the in vitro metabolism of [(14)C]CER was also examined. The metabolism of [(14)C]CER was inhibited by CsA with an IC(50) value of more than 30 microM. From these results, we conclude that the DDI between CER and CsA is mainly due to the inhibition of transporter (at least partly OATP2)-mediated uptake in the liver.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Cyclosporine	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Substrate Inhibitor	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Cyclosporine	Solute carrier organic anion transporter family member 1B1	Ki (nM)	238	N/A	N/A	Details