Nagaraju R Poola1, Michelle Kalis, Fotios M Plakogiannis, David R Taft. 1. Division of Pharmaceutics and Industrial Pharmacy, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201, USA.
Abstract
OBJECTIVE: To study the renal excretion and kidney accumulation of pentamidine, a potentially nephrotoxic compound, in the isolated perfused rat kidney (IPK). MATERIALS AND METHODS: IPK experiments (3-4 per treatment group) were conducted using male Sprague-Dawley rats (250-350 g). Dose proportionality studies were carried out over a pentamidine dosing range of 80-4000 microg, designed to target initial perfusate concentrations from 1 to 50 microg/mL. Separate interaction experiments were conducted between pentamidine (800 microg) and tetraethylammonium (dose 8000 microg) or dideoxyinosine (dose 80 microg). Inulin was used as a glomerular filtration rate (GFR) marker. Control (drug-naive) perfusions were also carried out. Pentamidine was analysed in perfusate, kidney and urine samples by HPLC. Inulin was measured by a colorimetric method. RESULTS: Pentamidine CLR (1.1 +/- 0.6 to 0.05 +/- 0.03 mL/min) and excretion ratio (3.6 +/- 1.5 to 0.56 +/- 0.15) significantly decreased over the range of doses studied. Significant reductions in viability parameters (GFR, Na reabsorption) were noted in kidneys perfused with high dose pentamidine (4000 microg). Tetraethylammonium co-administration reduced pentamidine renal excretion, resulting in significantly greater kidney accumulation of pentamidine and reduced kidney function. Dideoxyinosine administration had minimal effects on pentamidine disposition. CONCLUSIONS: Pentamidine renal transport involves a combination of mechanisms (filtration, secretion and passive reabsorption). Dose proportionality studies demonstrated non-linear excretion of pentamidine. Inhibition of pentamidine renal clearance by tetraethylammonium was consistent with decreased luminal transport. The detrimental effects of pentamidine on kidney function were the result of significant kidney accumulation of drug. The potential exists for drug-drug interactions between pentamidine and organic cations, increasing the risk of drug-induced nephrotoxicity.
OBJECTIVE: To study the renal excretion and kidney accumulation of pentamidine, a potentially nephrotoxic compound, in the isolated perfused rat kidney (IPK). MATERIALS AND METHODS: IPK experiments (3-4 per treatment group) were conducted using male Sprague-Dawley rats (250-350 g). Dose proportionality studies were carried out over a pentamidine dosing range of 80-4000 microg, designed to target initial perfusate concentrations from 1 to 50 microg/mL. Separate interaction experiments were conducted between pentamidine (800 microg) and tetraethylammonium (dose 8000 microg) or dideoxyinosine (dose 80 microg). Inulin was used as a glomerular filtration rate (GFR) marker. Control (drug-naive) perfusions were also carried out. Pentamidine was analysed in perfusate, kidney and urine samples by HPLC. Inulin was measured by a colorimetric method. RESULTS:PentamidineCLR (1.1 +/- 0.6 to 0.05 +/- 0.03 mL/min) and excretion ratio (3.6 +/- 1.5 to 0.56 +/- 0.15) significantly decreased over the range of doses studied. Significant reductions in viability parameters (GFR, Na reabsorption) were noted in kidneys perfused with high dose pentamidine (4000 microg). Tetraethylammonium co-administration reduced pentamidinerenal excretion, resulting in significantly greater kidney accumulation of pentamidine and reduced kidney function. Dideoxyinosine administration had minimal effects on pentamidine disposition. CONCLUSIONS:Pentamidine renal transport involves a combination of mechanisms (filtration, secretion and passive reabsorption). Dose proportionality studies demonstrated non-linear excretion of pentamidine. Inhibition of pentamidine renal clearance by tetraethylammonium was consistent with decreased luminal transport. The detrimental effects of pentamidine on kidney function were the result of significant kidney accumulation of drug. The potential exists for drug-drug interactions between pentamidine and organic cations, increasing the risk of drug-induced nephrotoxicity.
Authors: Horacio A Priestap; M Cecilia Torres; Robert A Rieger; Kathleen G Dickman; Tomoko Freshwater; David R Taft; Manuel A Barbieri; Charles R Iden Journal: Chem Res Toxicol Date: 2011-12-14 Impact factor: 3.739