Isolated rat kidney perfused with dextran and bovine serum albumin: a stable model for investigating renal drug handling.
BACKGROUND
The rat isolated perfused kidney (IPK) preparation is a very useful model for pharmacokinetic and pharmacologic studies. Bovine serum albumin (BSA) is the oncotic agent used most commonly in IPK models, but the protein is expensive and varies significantly in quality. The present study evaluated the use of dextran to replace a large proportion of BSA as the oncotic agent, to establish a more reliable and economic IPK model for pharmacokinetic studies.


METHODS
The right kidneys of male Sprague-Dawley rats were isolated and perfused in recirculating mode with Krebs-Henseleit pH 7.4 buffer containing amino acids, glucose and 65 g/l BSA (BSA group, n=11) or 6.5 g/l BSA plus 36 g/l dextran (dextran/BSA group, n=6). (14)C-Inulin was added to the perfusate to permit estimation of glomerular filtration rate (GFR). An antiviral guanosine analogue, AM188, was administered to the IPK perfusate to investigate its renal disposition. During the 130-min experimental period, urine was collected in 10-min intervals and perfusate was collected at the midpoint of these intervals.


RESULTS
The kidney functional parameters were generally better and more stable in the dextran/BSA IPKs when compared to the BSA group. At a similar perfusate flow rate, the IPKs in the dextran/BSA group exhibited lower renal artery perfusion pressure, a higher GFR, and more extensive tubular reabsorption of water, glucose, and sodium. These functional parameters were acceptable and stable throughout the whole experimental period in the dextran/BSA group. The renal clearance of AM188 was higher in the dextran/BSA group compared with that in the BSA group.


CONCLUSIONS
Using a large proportion of dextran and a small proportion of BSA as oncotic agent in perfusate provides an improved IPK preparation. This offers a reliable and economic rat IPK model for pharmacokinetic studies.
Centre for Pharmaceutical Research, School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, North Terrace, Adelaide, SA 5000, Australia.
Jiping
J
Wang
Roger L
RL
Nation
Allan M
AM
Evans
Susan
S
Cox
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics; D002417:Cattle; D003911:Dextrans / Q000493:pharmacokinetics*; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D010477:Perfusion / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D003911:Dextrans; D012710:Serum Albumin, Bovine