Abstract
To clarify which process in renal secretion is responsible for the stereoselective renal secretion of organic anions, the renal handling of enantiomers of 5-monomethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (MBCA) was studied by the multiple-indicator dilution method, using isolated perfused rat kidney. After bolus injection of (R)-(+)-[14C]MBCA or (S)-(−)-[14C]MBCA into the renal artery, the outflow patterns for the perfusate and the urinary excretion rate profiles were estimated by statistical moment analysis. AUC values and mean transit times in kidney for the MBCA enantiomers indicated that (R)-(+)-MBCA was excreted much more extensively in urine and that it had a higher affinity for renal tissue than did (S)-(−)-MBCA. A significantly larger intrinsic clearance of secretion for (R)-(+)-MBCA attested to the R-(+)-preferential renal secretion. The uptake rate constant across the basolateral membrane, the ratio of the uptake rate constant to the free fraction in the perfusate, and the intracellular distribution volume were significantly larger for (R)-(+)-MBCA than for (S)-(−)-MBCA, indicating that uptake across the basolateral membrane and intracellular distribution wereR-(+)-preferential. However, the mean time across renal epithelial cells for secreted molecules, the single-pass mean residence time in renal epithelial cells, and the rate constant for secretion across the brush-border membrane were not significantly different between enantiomers. The simultaneous presence of (R)-(+)-MBCA decreased the intrinsic clearance of secretion, the ratio of the uptake rate constant to the free fraction in the perfusate, and the intracellular distribution volume for (S)-(−)-[14C]MBCA, although the secretion rate constant, the mean time across renal epithelial cells for secreted molecules, and the single-pass mean residence time in renal epithelial cells were not influenced by (R)-(+)-MBCA, confirming that uptake across the basolateral membrane and intracellular distribution were stereoselective processes.
Footnotes
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Send reprint requests to: Dr. K. Higaki, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1–1-1 Tsushima-naka, Okayama, 700, Japan.
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↵1 Present address: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1–1-1 Tsushima-naka, Okayama, 700, Japan.
- Abbreviations used are::
- DBCA
- 5-dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid
- MBCA
- 5-monomethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid
- MTTc
- mean transit time in cannula
- MTTkidney
- mean transit time in kidney
- MTTurine
- mean urinary excretion time
- CLint,s
- intrinsic clearance of secretion
- BLM
- basolateral membrane
- BBM
- brush-border membrane
- BSA
- bovine serum albumin
- KRB buffer
- Krebs-Ringer bicarbonate buffer
- T̅ cell
- mean time across renal epithelial cells for secreted molecules
- T̅ cell,sp
- single-pass mean residence time in renal epithelial cells
- Vd,kidney
- steady-state distribution volume in kidney
- Vd,cell
- intracellular distribution volume
- PAH
- p-aminohippuric acid
- fp
- free fraction in perfusate
- GFR
- glomerular filtration rate
- Received May 12, 1997.
- Accepted November 7, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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