Impact of the induced organic anion transporter 1 (Oat1) renal expression by furosemide on the pharmacokinetics of organic anions

• Published in: Nephrology (Carlton, Vic.) Vic.), 2017-08, Vol.22 (8), p.642-648
• Main Authors: Severin, María Julia, Hazelhoff, María Herminia, Bulacio, Romina Paula, Mamprin, María Eugenia, Brandoni, Anabel, Torres, Adriana Mónica
• Format: Article
• Language: English
• Subjects: Animals; Anions; ATP-Binding Cassette Transporters - drug effects; ATP-Binding Cassette Transporters - metabolism; Body weight; Drug Interactions; Femoral artery; Femur; Furosemide; Furosemide - administration & dosage; Furosemide - pharmacology; Injections, Intravenous; Injections, Subcutaneous; Kidney - drug effects; Kidney - metabolism; Kidneys; Male; Metabolic Clearance Rate; Models, Biological; Mrp2; Multidrug resistance; Oat1; organic anion; Organic Anion Transport Protein 1 - drug effects; Organic Anion Transport Protein 1 - metabolism; p-Aminohippurate; p-Aminohippuric Acid - administration & dosage; p-Aminohippuric Acid - blood; p-Aminohippuric Acid - pharmacokinetics; p-Aminohippuric Acid - urine; Pharmacokinetics; Plasma levels; Polycyclic aromatic hydrocarbons; Rats, Wistar; Renal Elimination - drug effects; Rodents; Sodium Potassium Chloride Symporter Inhibitors - administration & dosage; Sodium Potassium Chloride Symporter Inhibitors - pharmacology; Up-Regulation; Urine; Western blotting
• ISSN: 1320-5358; 1440-1797
• DOI: 10.1111/nep.12838

Aim 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. Summary at a Glance Authors investigated whether the pretreatment with furosemide alters the pharmacokinetics of an organic anion model such as p‐aminohippurate (PAH) in rats. Furosemide‐treated group showed higher PAH plasma levels, a lower systemic clearance and a lower elimination rate constant from the peripheral compartment, indicating that PAH renal elimination was decreased. PAH levels in renal tissue were significantly elevated and PAH levels in urine appeared to be significantly lower in treated animals than in control animals. The results become highly relevant since the treatment with this diuretic might generate significant alterations in the pharmacokinetics of different organic anion dru