JAC Advance Access originally published online on July 29, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 397-404
© 2003 The British Society for Antimicrobial Chemotherapy
Characterization of pentamidine excretion in the isolated perfused rat kidney
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; 2 Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA
Received 16 October 2002; returned 27 March 2003; revised 8 April 2003; accepted 28 May 2003
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 µg, designed to target initial perfusate concentrations from 1 to 50 µg/mL. Separate interaction experiments were conducted between pentamidine (800 µg) and tetraethylammonium (dose 8000 µg) or dideoxyinosine (dose 80 µg). 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 µg). 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.
Keywords: pentamidine, renal transport, renal excretion, nephrotoxicity, kidney accumulation
* Present address. Berlex Laboratories Inc., Montville, NJ 07045, USA.
Corresponding author. Tel: +1-718-488-1632; Fax: +1-718-780-4586; E-mail: dtaft{at}liu.edu