title: Influence of serum in hemodialysis patients on the expression of intestinal and hepatic transporters for the excretion of pravastatin.
abstract: It is known that the lipid-lowering agent pravastatin, which is not metabolized by cytochrome P450, is eliminated as an unchanged drug in bile and urine. It is interesting to note that the non-renal clearance of pravastatin in end-stage renal failure patients is decreased compared with that of healthy volunteers. This study investigated the influence of uremic serum and toxins on the transport mechanisms of pravastatin to elucidate the cause of decreased non-renal clearance in end-stage renal failure patients. Caco-2 and Hep3B cells were used as models of intestinal epithelial cells and hepatocytes respectively. Normal and uremic serum were deproteinized by treatment with methanol. 3-Carboxy-4-methyl-5propyl-2-furanpropanoic acid (CMPF), hippuric acid, indole-3-acetic acid, 3-indoxyl sulfate, and p-cresol were chosen as uremic toxins. Uremic serum-treated Caco-2 cells exhibited significantly increased accumulation of pravastatin and significantly decreased expression of MRP2 mRNA compared with normal serum-treated Caco-2 cells. In addition, the expression of MRP2 mRNA tended to decrease in cells treated with CMPF, indole-3-acetic acid, or 3-indoxyl sulfate. Uremic serum-treated Hep3B cells showed a significantly decreased initial uptake rate of pravastatin; furthermore, the expressions of OATP1B1 and OATP2B1 mRNA were decreased compared to normal serum-treated Hep3B cells. These results suggest that the decrease in the non-renal clearance of pravastatin in end-stage renal failure patients is partly induced by the downregulation of intestinal MRP2 and hepatic OATP1B1 and/or OATP2B1 by various uremic toxins in end-stage renal failure patients.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hatozaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Shima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yokota
authors.forename: Taku
authors.initials: T
authors.lastname: Furukubo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Izumi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamakawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Minegaki
authors.forename: Kohshi
authors.initials: K
authors.lastname: Nishiguchi
mesh_terms: D001692:Biological Transport; D018938:Caco-2 Cells; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D007676:Kidney Failure, Chronic / Q000503:physiopathology / Q000628:therapy*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D017035:Pravastatin / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000378:metabolism; D006435:Renal Dialysis; D014511:Uremia / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D017035:Pravastatin; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C450859:SLCO2B1 protein, human