BIOMAT Database Logo BIOMAT Database Logo

Organic Anion-Transporting Polypeptide and Efflux Transporter-Mediated Hepatic Uptake and Biliary Excretion of Cilostazol and Its Metabolites in Rats and Humans. 2017

Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Liaoning, China.

Cilostazol undergoes extensive liver metabolism. However, the transporter-mediated hepatic disposition of cilostazol remains unknown. The present study was performed to investigate the hepatic uptake and biliary excretion of cilostazol and its metabolites (OPC-13015 and OPC-13213) using rat liver and human transporter-transfected cells in vitro. Cilostazol uptake by rat liver slices and isolated rat hepatocytes exhibited time-, concentration-, and temperature dependency and was decreased by Oatp inhibitors, which suggested that Oatp was involved in the hepatic uptake of cilostazol. Cilostazol uptake in rat hepatocytes, OATP1B1-, and OATP1B3-HEK293 cells indicated a saturable process with Km values of 2.7 μM, 17.7 μM, and 2.7 μM, respectively. Epigallocatechin gallate, cyclosporin A, rifampicin, and telmisartan inhibited cilostazol uptake in OATP1B1/1B3-HEK293 cells with Ki values close to their clinical plasma concentration, which suggested possible drug-drug interactions in humans via OATP1B1/1B3. Moreover, the cumulative biliary excretion of cilostazol and OPC-13015 was significantly decreased by quinidine, bilirubin, and novobiocin in perfused rat liver, but OPC-13213 biliary excretion was only inhibited by novobiocin, which suggested that the efflux transporters Mrp2, Bcrp, and P-gp were involved in the biliary excretion of cilostazol and its metabolites. Our findings indicated that multiple transporters were involved in the hepatic disposition of cilostazol and its metabolites.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008297 Male Males
D010975 Platelet Aggregation Inhibitors Drugs or agents which antagonize or impair any mechanism leading to blood platelet aggregation, whether during the phases of activation and shape change or following the dense-granule release reaction and stimulation of the prostaglandin-thromboxane system. Antiaggregants, Platelet,Antiplatelet Agent,Antiplatelet Agents,Antiplatelet Drug,Blood Platelet Aggregation Inhibitor,Blood Platelet Antagonist,Blood Platelet Antiaggregant,PAR-1 Antagonists,Platelet Aggregation Inhibitor,Platelet Antagonist,Platelet Antagonists,Platelet Antiaggregant,Platelet Antiaggregants,Platelet Inhibitor,Protease-Activated Receptor-1 Antagonists,Antiplatelet Drugs,Blood Platelet Aggregation Inhibitors,Blood Platelet Antagonists,Blood Platelet Antiaggregants,Platelet Inhibitors,Agent, Antiplatelet,Aggregation Inhibitor, Platelet,Antagonist, Blood Platelet,Antagonist, Platelet,Antiaggregant, Blood Platelet,Antiaggregant, Platelet,Drug, Antiplatelet,Inhibitor, Platelet,Inhibitor, Platelet Aggregation,PAR 1 Antagonists,Platelet Antagonist, Blood,Platelet Antiaggregant, Blood,Protease Activated Receptor 1 Antagonists
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000074542 Solute Carrier Organic Anion Transporter Family Member 1B3 A sodium-independent organic anion transporter that functions in the uptake of various drugs and endogenous compounds including ESTRADIOL; TAUROCHOLATE; LEUKOTRIENE C4; and METHOTREXATE. It also functions in clearing BILE ACIDS and organic anions from the liver. Mutations in the SLCO1B3 gene are associated with Rotor Type HYPERBILIRUBINEMIA. Liver-Specific Organic Anion Transporter-2,OATP1B3 Protein,OATP8 Protein,SLC21A8 Protein,SLCO1B3 Protein,Solute Carrier Family 21 Member 8 Protein,Liver Specific Organic Anion Transporter 2
D000077407 Cilostazol A quinoline and tetrazole derivative that acts as a phosphodiesterase type 3 inhibitor, with anti-platelet and vasodilating activity. It is used in the treatment of PERIPHERAL VASCULAR DISEASES; ISCHEMIC HEART DISEASE; and in the prevention of stroke. 6-(4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolinone,OPC 13013,OPC-13013,Pletal
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001692 Biological Transport The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments. Transport, Biological,Biologic Transport,Transport, Biologic
D013777 Tetrazoles

Related Publications

Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake of Glucuronide Metabolites of Androgens.
September 2020, Molecular pharmacology,
Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Organic Anion Transporting Polypeptide (OATP) 1B3 is a Significant Transporter for Hepatic Uptake of Conjugated Bile Acids in Humans.
January 2023, Cellular and molecular gastroenterology and hepatology,
Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake.
March 2011, Pharmacological reviews,
Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans.
October 2005, Drug metabolism and disposition: the biological fate of chemicals,
Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data.
September 2014, Drug metabolism and disposition: the biological fate of chemicals,
Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Intestinal ischemia-reperfusion suppresses biliary excretion of hepatic organic anion transporting polypeptides substrate.
January 2013, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques,
Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Organic anion-transporting polypeptide (OATP) transporter family and drug disposition.
November 2003, European journal of clinical investigation,
Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Clinical Relevance of Organic Anion Transporting Polypeptide 1B-Mediated Hepatic Uptake for High-Permeability Drugs: A Perspective.
September 2022, Clinical pharmacology and therapeutics,
Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Involvement of organic anion-transporting polypeptides and organic cation transporter in the hepatic uptake of jatrorrhizine.
April 2020, Xenobiotica; the fate of foreign compounds in biological systems,
Chong Wang, and Xiaokui Huo, and Changyuan Wang, and Qiang Meng, and Zhihao Liu, and Pengyuan Sun, and Jian Cang, and Huijun Sun, and Kexin Liu
Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats.
April 1997, The Journal of pharmacology and experimental therapeutics,
Copied contents to your clipboard!