Inhibition of Transporter-Mediated Hepatic Uptake as a Mechanism for Drug-Drug Interaction between Cerivastatin and Cyclosporin A

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 [14C]CER into human hepatocytes prepared from three different donors was examined. Kinetic analyses revealedK m values for the uptake of [14C]CER within the range of 3 to 18 μM, 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 withK i values of 0.3 to 0.7 μM. The uptake of [14C]CER was also examined in human organic anion transporting polypeptide-2 (OATP2)-expressing Madin-Darby canine kidney cells (MDCKII). Saturable OATP2-mediated uptake of [14C]CER was observed and was also inhibited by CsA, with a K i value of 0.2 μM. 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 [14C]CER was also examined. The metabolism of [14C]CER was inhibited by CsA with an IC50value of more than 30 μM. 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.

[1]  Y. Sugiyama,et al.  QUANTITATIVE PREDICTION: METABOLISM, TRANSPORT IN THE LIVER , 1999 .

[2]  L Fritsche,et al.  Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine‐treated kidney transplant recipients , 1999, Clinical pharmacology and therapeutics.

[3]  V. Sasseville,et al.  A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2) , 1999, The Journal of Biological Chemistry.

[4]  Albert P. Li,et al.  Isolation and culturing of hepatocytes from human livers , 1992 .

[5]  H. Yawo,et al.  Identification of a Novel Gene Family Encoding Human Liver-specific Organic Anion Transporter LST-1* , 1999, The Journal of Biological Chemistry.

[6]  J. Miners,et al.  The xenobiotic inhibitor profile of cytochrome P4502C8. , 2000, British journal of clinical pharmacology.

[7]  M. Waye,et al.  Assignment1 of liver-specific organic anion transporter (SLC22A7) to human chromosome 6 bands p21.2→p21.1 using radiation hybrids , 2000, Cytogenetic and Genome Research.

[8]  Yuichi Sugiyama,et al.  Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[9]  A Ward,et al.  Pentoxifylline , 1987, Drugs.

[10]  P. A. Todd,et al.  Gemfibrozil , 2012, Drugs.

[11]  Y. Sugiyama,et al.  Contribution of organic anion transporting polypeptide to uptake of its possible substrates into rat hepatocytes. , 1999, The Journal of pharmacology and experimental therapeutics.

[12]  Y. Sugiyama,et al.  Inhibition of biliary excretion of methotrexate by probenecid in rats: quantitative prediction of interaction from in vitro data. , 2001, The Journal of pharmacology and experimental therapeutics.

[13]  K. Ochmann,et al.  PHARMACOKINETICS AND DISPOSITION , 1998 .

[14]  Yuichi Sugiyama,et al.  Drug-Drug Interactions Involving the Membrane Transport Process , 2001 .

[15]  K. Korzekwa,et al.  Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8. , 1994, Cancer research.

[16]  D. Keppler,et al.  A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[17]  H. Yamazaki,et al.  A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[18]  A. Gavazzi,et al.  Altered disposition of pravastatin following concomitant drug therapy with cyclosporin A in transplant recipients. , 1993, Transplantation proceedings.

[19]  T. Abe,et al.  Transcellular Transport of Organic Anions Across a Double-transfected Madin-Darby Canine Kidney II Cell Monolayer Expressing Both Human Organic Anion-transporting Polypeptide (OATP2/SLC21A6) and Multidrug Resistance-associated Protein 2 (MRP2/ABCC2)* , 2002, The Journal of Biological Chemistry.

[20]  Y. Sugiyama,et al.  Selective inhibition of human cytochrome P450 3A4 by N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-(1, 1-dimethylethylaminocarbonyl)-4-[(furo[2, 3-b]pyridin-5-yl)methyl]piperazin-1-yl]-4(S)-hydroxy-2(R)-phenylmethy lpentanamide and P-glycoprotein by valspodar in gene transfectant systems. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[21]  T. Tokui,et al.  Carrier-mediated uptake of pravastatin by rat hepatocytes in primary culture. , 1992, Biochemical pharmacology.

[22]  D. Keppler,et al.  Localization and Genomic Organization of a New Hepatocellular Organic Anion Transporting Polypeptide* , 2000, The Journal of Biological Chemistry.

[23]  H. Barratt.  UK government launches anti-tobacco campaign for Asians , 2001, BMJ : British Medical Journal.

[24]  Y. Sugiyama,et al.  Contribution of sodium taurocholate co-transporting polypeptide to the uptake of its possible substrates into rat hepatocytes. , 1998, The Journal of pharmacology and experimental therapeutics.

[25]  B. Ma,et al.  Mechanistic studies on metabolic interactions between gemfibrozil and statins. , 2002, The Journal of pharmacology and experimental therapeutics.

[26]  W. Mück.  Clinical Pharmacokinetics of Cerivastatin , 2000, Clinical pharmacokinetics.

[27]  F. Charatan.  Bayer decides to withdraw cholesterol lowering drug , 2001, BMJ : British Medical Journal.

[28]  Y. Sugiyama,et al.  Drug transporters: their role and importance in the selection and development of new drugs. , 2002, Drug metabolism and pharmacokinetics.

[29]  J. Nezu,et al.  Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. , 2000, Biochemical and biophysical research communications.

[30]  T. Abe,et al.  Comparative Inhibitory Effects of Different Compounds on Rat Oatp1 (Slc21a1)- and Oatp2 (Slc21a5)-Mediated Transport , 2002, Pharmaceutical Research.

[31]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[32]  A. Li,et al.  Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. , 1999, Chemico-biological interactions.

[33]  Y. Sugiyama,et al.  Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. , 1998, Pharmacological reviews.

[34]  Y. Sugiyama,et al.  Prediction of In Vivo Interaction Between Triazolam and Erythromycin Based on In Vitro Studies Using Human Liver Microsomes and Recombinant Human CYP3A4 , 2000, Pharmaceutical Research.

[35]  M Lemaire,et al.  Role of lipoproteins and erythrocytes in the in vitro binding and distribution of cyclosporin A in the blood , 1982, The Journal of pharmacy and pharmacology.

[36]  Y. Horsmans,et al.  Clinical Pharmacokinetics of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors , 1996, Clinical pharmacokinetics.

[37]  Y. Yoshimura,et al.  Carrier-Mediated Uptake of Cerivastatin in Primary Cultured Rat Hepatocytes , 2000 .

[38]  T. Abe,et al.  Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. , 2001, The Journal of pharmacology and experimental therapeutics.

[39]  M. Moghadasian.  Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. , 1999, Life Science.

[40]  T Nakagawa,et al.  A pharmacokinetic analysis program (multi) for microcomputer. , 1981, Journal of pharmacobio-dynamics.

[41]  F. Charatan.  Exercise and diet reduce risk of diabetes, US study shows , 2001, BMJ : British Medical Journal.