Stereoselective pharmacokinetics of a chiral organic anion in rats - Analysis of its kinetics in liver and kidney

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Abstract

DBCA, 5-dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2- carboxylic acid, is a racemic antonio compound. Its stereoselective pharmacokinetics was suggested to be attributed to stereoselective hepatic and renal elimination based on in vivo studies. We have tried to clarify and estimate the stereoselectivity of hepatic and renal elimination by using of single-pass perfused organ preparations. Liver perfusion study of racemic DBCA showed R(+)-predominant extraction and generation of MBCA, 5monomethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid, the major metabolite of DBCA. Pharmacokinetic analysis based on a well- stirred model with diffusional clearance (CLd) across the sinusoidal membrane revealed the possibility of stereoselectivity not in the biliary excretion but in the hepatic transport and N-monodemethylation (R(+)-predominant). A single-pass kidney perfusion study under constant perfusion pressure indicated highly selective elimination for (R)(+)-DBCA. Plotting of fractional excretion (FE) ratios of DBCA enantiomers to (R)(+).MBCA against that of (R)(+)-MBCA suggests that the actual FE for (R)(+)-DBCA is two times larger than that for (S)(-)-DBCA. Thus, DBCA seemed to be stereoselectively secreted in the proximal tubules, although little information is available on the stereoselective renal secretion of acidic chiral compounds. Moreover, we also tried to clarify the stereoselective process in the renal tubular secretion of organic anions in the use of MBCA not metabolized further and the stereoselective uptake of MBCA from the basolateral membrane could be testified by the multiple indicator dilution studies using the isolated perfused kidney.

Original languageEnglish
Pages (from-to)48-85
Number of pages38
JournalAnnual Report of Shionogi Research Laboratory
Issue number46
Publication statusPublished - 1996

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Anions
Pharmacokinetics
Kidney
Liver
Perfusion
S 8666
Membranes
Carboxylic Acids
3-methoxybutylcyanoacrylate
Pressure
Hepatobiliary Elimination
Renal Elimination

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

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title = "Stereoselective pharmacokinetics of a chiral organic anion in rats - Analysis of its kinetics in liver and kidney",
abstract = "DBCA, 5-dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2- carboxylic acid, is a racemic antonio compound. Its stereoselective pharmacokinetics was suggested to be attributed to stereoselective hepatic and renal elimination based on in vivo studies. We have tried to clarify and estimate the stereoselectivity of hepatic and renal elimination by using of single-pass perfused organ preparations. Liver perfusion study of racemic DBCA showed R(+)-predominant extraction and generation of MBCA, 5monomethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid, the major metabolite of DBCA. Pharmacokinetic analysis based on a well- stirred model with diffusional clearance (CLd) across the sinusoidal membrane revealed the possibility of stereoselectivity not in the biliary excretion but in the hepatic transport and N-monodemethylation (R(+)-predominant). A single-pass kidney perfusion study under constant perfusion pressure indicated highly selective elimination for (R)(+)-DBCA. Plotting of fractional excretion (FE) ratios of DBCA enantiomers to (R)(+).MBCA against that of (R)(+)-MBCA suggests that the actual FE for (R)(+)-DBCA is two times larger than that for (S)(-)-DBCA. Thus, DBCA seemed to be stereoselectively secreted in the proximal tubules, although little information is available on the stereoselective renal secretion of acidic chiral compounds. Moreover, we also tried to clarify the stereoselective process in the renal tubular secretion of organic anions in the use of MBCA not metabolized further and the stereoselective uptake of MBCA from the basolateral membrane could be testified by the multiple indicator dilution studies using the isolated perfused kidney.",
author = "Kazutaka Higaki",
year = "1996",
language = "English",
pages = "48--85",
journal = "Annual Report of Shionogi Research Laboratory",
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TY - JOUR

T1 - Stereoselective pharmacokinetics of a chiral organic anion in rats - Analysis of its kinetics in liver and kidney

AU - Higaki, Kazutaka

PY - 1996

Y1 - 1996

N2 - DBCA, 5-dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2- carboxylic acid, is a racemic antonio compound. Its stereoselective pharmacokinetics was suggested to be attributed to stereoselective hepatic and renal elimination based on in vivo studies. We have tried to clarify and estimate the stereoselectivity of hepatic and renal elimination by using of single-pass perfused organ preparations. Liver perfusion study of racemic DBCA showed R(+)-predominant extraction and generation of MBCA, 5monomethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid, the major metabolite of DBCA. Pharmacokinetic analysis based on a well- stirred model with diffusional clearance (CLd) across the sinusoidal membrane revealed the possibility of stereoselectivity not in the biliary excretion but in the hepatic transport and N-monodemethylation (R(+)-predominant). A single-pass kidney perfusion study under constant perfusion pressure indicated highly selective elimination for (R)(+)-DBCA. Plotting of fractional excretion (FE) ratios of DBCA enantiomers to (R)(+).MBCA against that of (R)(+)-MBCA suggests that the actual FE for (R)(+)-DBCA is two times larger than that for (S)(-)-DBCA. Thus, DBCA seemed to be stereoselectively secreted in the proximal tubules, although little information is available on the stereoselective renal secretion of acidic chiral compounds. Moreover, we also tried to clarify the stereoselective process in the renal tubular secretion of organic anions in the use of MBCA not metabolized further and the stereoselective uptake of MBCA from the basolateral membrane could be testified by the multiple indicator dilution studies using the isolated perfused kidney.

AB - DBCA, 5-dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2- carboxylic acid, is a racemic antonio compound. Its stereoselective pharmacokinetics was suggested to be attributed to stereoselective hepatic and renal elimination based on in vivo studies. We have tried to clarify and estimate the stereoselectivity of hepatic and renal elimination by using of single-pass perfused organ preparations. Liver perfusion study of racemic DBCA showed R(+)-predominant extraction and generation of MBCA, 5monomethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid, the major metabolite of DBCA. Pharmacokinetic analysis based on a well- stirred model with diffusional clearance (CLd) across the sinusoidal membrane revealed the possibility of stereoselectivity not in the biliary excretion but in the hepatic transport and N-monodemethylation (R(+)-predominant). A single-pass kidney perfusion study under constant perfusion pressure indicated highly selective elimination for (R)(+)-DBCA. Plotting of fractional excretion (FE) ratios of DBCA enantiomers to (R)(+).MBCA against that of (R)(+)-MBCA suggests that the actual FE for (R)(+)-DBCA is two times larger than that for (S)(-)-DBCA. Thus, DBCA seemed to be stereoselectively secreted in the proximal tubules, although little information is available on the stereoselective renal secretion of acidic chiral compounds. Moreover, we also tried to clarify the stereoselective process in the renal tubular secretion of organic anions in the use of MBCA not metabolized further and the stereoselective uptake of MBCA from the basolateral membrane could be testified by the multiple indicator dilution studies using the isolated perfused kidney.

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JO - Annual Report of Shionogi Research Laboratory

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