Impact of the induced organic anion transporter 1 (Oat1) renal expression by furosemide on the pharmacokinetics of organic anions.
OBJECTIVE
Furosemide is a loop diuretic. Different authors demonstrated that continuous administration of furosemide modulates the expression of organic anion transporters. This study was undertaken to simultaneously evaluate the effects of furosemide pretreatment on organic anion transporter 1 (Oat1) and multidrug resistance protein 2 (Mrp2) renal expressions, on p-aminohippurate (PAH) pharmacokinetics and on renal and urinary PAH levels in rats.


METHODS
Male Wistar rats were treated with furosemide (6 mg/100 g body weight per day, subcutaneously, 4 days) (treated group) or saline (control group). On the fifth day, PAH was administered as a bolus infusion in the femoral vein, and plasma samples were obtained from femoral artery at different time points. PAH levels in renal tissue and urine were also assessed. Renal Oat1 and Mrp2 expressions were evaluated by western blotting.


RESULTS
Furosemide pretreatment increased both the expression of Oat1 and Mrp2. PAH plasma concentrations decreased following a biexponential function. The furosemide-treated group showed higher PAH plasma levels, a lower systemic clearance and elimination rate constant from the peripheral compartment, indicating that PAH renal elimination was decreased. PAH levels in renal tissue were significantly elevated and in urine appeared to be significantly lower as compared with control animals.


CONCLUSIONS
Furosemide pretreatment caused a significant decrease of PAH renal elimination, despite Oat1 and Mrp2 augmented renal expression. The goal of the present study is the addition of important information in the wide gap of knowledge that exists about drug-drug interactions. Because of furosemide worldwide use, the data obtained are interesting and useful in terms of translation to clinical practice.
Pharmacology, Faculty of Biochemical and Pharmaceutical Sciences, Rosario National University, CONICET, Rosario, Argentina.
María Julia
MJ
Severin
Pharmacology, Faculty of Biochemical and Pharmaceutical Sciences, Rosario National University, CONICET, Rosario, Argentina.
María Herminia
MH
Hazelhoff
Pharmacology, Faculty of Biochemical and Pharmaceutical Sciences, Rosario National University, CONICET, Rosario, Argentina.
Romina Paula
RP
Bulacio
Pharmacology, Faculty of Biochemical and Pharmaceutical Sciences, Rosario National University, CONICET, Rosario, Argentina.
María Eugenia
ME
Mamprin
Pharmacology, Faculty of Biochemical and Pharmaceutical Sciences, Rosario National University, CONICET, Rosario, Argentina.
Anabel
A
Brandoni
Pharmacology, Faculty of Biochemical and Pharmaceutical Sciences, Rosario National University, CONICET, Rosario, Argentina.
Adriana Mónica
AM
Torres
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004347:Drug Interactions; D005665:Furosemide / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D027362:Organic Anion Transport Protein 1 / Q000187:drug effects* / Q000378:metabolism; D017208:Rats, Wistar; D065667:Renal Elimination / Q000187:drug effects; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation; D010130:p-Aminohippuric Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D027362:Organic Anion Transport Protein 1; C421043:Slc22a6 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D005665:Furosemide; D010130:p-Aminohippuric Acid
Mrp2; Oat1; furosemide; organic anion; pharmacokinetics