title: Aspirin and probenecid inhibit organic anion transporter 3-mediated renal uptake of cilostazol and probenecid induces metabolism of cilostazol in the rat.
abstract: This study aimed to evaluate the transporter-mediated renal excretion mechanism for cilostazol and to characterize the mechanism of drug-drug interaction (DDI) between cilostazol and aspirin or probenecid. Concentrations of cilostazol and its metabolites OPC-13015 [6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-2(1H)-quinolinone] and OPC-13213 [3,4-dihydro-6-[4-[1-(trans-4-hydroxycyclohexyl)-1H-tetrazol-5-yl]butoxy]-2-(1H)-quinolinone] in rat biologic or cell samples were measured by liquid chromatography-tandem mass spectrometry. Coadministration with probenecid, benzylpenicillin, or aspirin decreased the cumulative urinary excretion of cilostazol and renal clearance. Concentrations of cilostazol and OPC-13213 in plasma decreased, and the concentration of OPC-13015 increased in the presence of probenecid. By contrast, rat plasma cilostazol, in combination with benzylpenicillin or aspirin, sharply increased, and concentrations of OPC-13015 and OPC-13213 did not change. In urine, OPC-13015 was below the level of detection. The cumulative urinary excretion of OPC-13213 decreased in the presence of probenecid, benzylpenicillin, or aspirin. Cilostazol was distributed in the kidney and liver, with tissue to plasma partition coefficient (Kp) values of 8.4 ml/g and 16.3 ml/g, respectively. Probenecid and aspirin reduced cilostazol distribution in the kidney. Probenecid did not affect cilostazol metabolism in the kidney but increased cilostazol metabolism in the liver, and aspirin had no effect on cilostazol metabolism. Benzylpenicillin, aspirin, and cyclo-trans-4-l-hydroxyprolyl-l-serine (JBP485) reduced cilostazol uptake in kidney slices and human organic anion transporter 3 (hOAT3)-human embryonic kidney 293 (HEK293) cells, whereas p-aminohippuric acid did not. Compared with the vector, hOAT3-HEK293 cells accumulated more cilostazol, whereas hOAT1-HEK293 cells did not. OAT3 and Oat3 play a major role in cilostazol renal excretion, whereas OAT1 and Oat1 do not. Oat3 and Cyp3a are both targets of the DDI between cilostazol and probenecid. Aspirin inhibits OAT3-mediated uptake of cilostazol and does not influence cilostazol metabolism.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy (Cho.W., Cha.W., Q.L., Q.M., J.C., H.S., J.P., X.M., K.L.), and China Provincial Key Laboratory for Pharmacokinetics and Transport (Cha.W., Q.L., Q.M., J.C., H.S., J.P., X.M., X.H., K.L.), Dalian Medical University, Dalian, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.forename: Jian
authors.initials: J
authors.lastname: Cang
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.forename: Xiaochi
authors.initials: X
authors.lastname: Ma
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D000077407:Cilostazol; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009924:Organ Culture Techniques; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011339:Probenecid / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D029362:Organic Anion Transporters, Sodium-Independent; D013777:Tetrazoles; C114338:organic anion transport protein 3; D000077407:Cilostazol; D011339:Probenecid; D001241:Aspirin