Abstract
Previously, we have shown that the inhibition of the transporter-mediated hepatic uptake of cerivastatin (CER) by cyclosporin A (CsA) could, at least partly, explain a pharmacokinetic interaction between these drugs in humans. In the present study, we have examined the effect of CsA on the in vivo disposition of CER in rats and the in vitro uptake of [14C]CER in isolated rat hepatocytes in an attempt to evaluate the effect of inhibition of transporter-mediated hepatic uptake on the in vivo CER disposition. The steady-state plasma concentration of CER increased 1.4-fold when coadministered with CsA up to a steady-state blood concentration of 4 μM. Studies of [14C]CER uptake into isolated rat hepatocytes showed saturable transport, with the saturable portion accounting for more than 80% of the total uptake. CsA competitively inhibited the uptake of [14C]CER with a Ki of 0.3 μM. The IC50 for the uptake of [14C]CER in the absence and presence of rat plasma was 0.2 and 2.3 μM, respectively. The in vivo hepatic uptake of [14C]CER evaluated by the liver uptake index method was also inhibited by CsA in a dose-dependent manner. On the other hand, CsA did not inhibit the metabolism of [14C]CER in rat microsomes. The in vitro and in vivo correlation analysis revealed that this pharmacokinetic interaction between these drugs in rats could be quantitatively explained by the inhibition of transporter-mediated hepatic uptake. Thus, this drug-drug interaction in rats is predominantly caused by the transporter-mediated uptake process.
Footnotes
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This study was, in part, supported by the Grant-in-Aid for Young Scientists (B) provided by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Y.Sh.), Grant-in-Aid for the Advanced and Innovational Research program in Life Sciences (Y.Su.) and for the 21st Century Center of Excellence program provided by the Ministry of Education, Culture, Sports, Science and Technology, Japan (Y.Su.).
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ABBREVIATIONS: CER, cerivastatin; AUC, area under the plasma concentration-time curve; CLH, hepatic clearance; CLint, intrinsic hepatic clearance; CLint,all, overall intrinsic hepatic clearance; CLtot, total body clearance; CLuptake, uptake clearance; CsA, cyclosporin A; CYP2C8, cytochrome P450 2C8; DDI, drug-drug interaction; fb, blood unbound fraction; HEK, human embryonic kidney; HPLC, high performance liquid chromatography; IC50, inhibitor concentration to produce a 50% reduction in the transport; KHB, Krebs-Henseleit buffer; Ki, inhibition constant; Km, Michaelis constant; LUI, liver uptake index; OATP/Oatp, organic anion transporting polypeptide; Pdif, nonsaturable uptake clearance; PSu,efflux, membrane permeability clearance of the unbound drug for the efflux process; PSu,influx, membrane permeability clearance of the unbound drug for the influx process; SD rat, Sprague-Dawley rat; Vmax, maximum uptake rate.
- Received March 18, 2004.
- Accepted September 14, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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