Stereoselective renal tubular secretion of an organic anion in the isolated perfused rat kidney.
To clarify the stereoselective renal tubular secretion of an organic anion, renal excretion of 5-dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carbox yli c acid (DBCA), a racemic compound, was studied with a single-pass perfused rat kidney preparation under constant perfusion pressure (ca. 120 mm Hg). The steady-state renal extraction ratio of (R)-(+)-DBCA (0.134) was 10 times higher than that of (S)-(-)-DBCA (0.015), indicating high selectivity for (R)-(+)-DBCA. The urinary excretion rate and renal excretory clearance (CLrex) were 4 times larger for (R)-(+)-DBCA, and the unbound fraction in the perfusate also was higher for (R)-(+)-DBCA (R/S = 1.58). Fractional excretion (FE) and intrinsic clearance for tubular secretion (CLrsec,int) were about 3 times larger for (R)-(+)-DBCA than the antipode, showing the stereoselectively predominant secretion of (R)-(+)-DBCA. The N-monodemethylated metabolite, M-1, was found only for the R-(+)-enantiomer in the perfusate and urine, revealing highly stereoselective N-monodemethylation in the kidney. The CLrsec,int value for (R)-(+)-M-1 was 2.5 times larger than that for (R)-(+)-DBCA. The perfusion study using each enantiomer decreased R/S ratios of the extraction ratio (9.9), urinary excretion rate (3.9) and excretory clearance (3.9) in the perfusion of the racemate to 3.9, 2.1 and 2.1, respectively. No significant difference was found between (R)-(+)- and (S)-(-)-DBCA in FE and Clrsec,int. The declined stereoselectivity in renal excretion parameters may be due to competitive inhibition of the tubular secretion of (R)-(+)-DBCA by the (R)-(+)-M-1 formed which possessed greater secretion ability in the (R)-(+)-DBCA perfusion study, whereas (S)-(-)-DBCA was secreted without great inhibition by (S)-(-)-M-1 in the (S)-(-)-DBCA perfusion because of a small amount of generated metabolite. Plotting of FE ratios of DBCA enantiomers to (R)-(+)-M-1 against FE of (R)-(+)-M-1 suggests that the actual FE for (R)-(+)-DBCA was 2 times larger than that for (S)-(-)-DBCA, and that (S)-(-)-DBCA secretion was inhibited more easily by (R)-(+)-M-1.
Higaki
K
K
Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Kadono
K
K
Goto
S
S
Nakano
M
M
D000818:Animals; D004232:Diuretics / Q000493:pharmacokinetics*; D004347:Drug Interactions; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013449:Sulfonamides / Q000493:pharmacokinetics*
D004232:Diuretics; D013449:Sulfonamides; C052960:S 8666