ArticlePharmaceutical research1999
Determination of the rate-limiting step in the hepatic elimination of YM796 by isolated rat hepatocytes.
Article in Pharmaceutical research, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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0 citing papers in PubMed, 9 citations in OpenAlex.
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Authors and funding
3 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
purposeThe membrane permeability clearance and intrinsic metabolic clearance of a drug in the liver were estimated using isolated rat hepatocytes, and the rate-limiting step in the overall intrinsic clearance of the drug in vivo was investigated. For this purpose, an anti-dementia drug, (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro [4,5] decane-L-tartarate monohydrate (YM796) was used as a model drug.
methodsThe parent drug and its metabolites in both medium and cells were separated by thin-layer chromatography (TLC). The total amount of drug taken up by hepatocytes and the total amount of metabolites were plotted against the AUC of YM796 in the medium or cells to obtain the kinetic parameters.
resultsWhile the influx clearance (PS(inf)) through the sinusoidal membrane defined in terms of YM796 concentration in the medium was almost constant, irrespective of the concentration of YM796 in the medium, the intrinsic metabolic clearance (CL(int)) and the efflux clearance (PS(eff)) defined in terms of the total concentration of YM796 in the cells markedly decreased and increased, respectively, as the concentration of YM796 increased. The overall intrinsic metabolic clearance (CL(int,all), defined in terms of the YM796 concentration in the medium, corresponding to the hepatic intrinsic clearance obtained from the in vivo pharmacokinetic data on the drug, was comparable with PS(inf) at low concentrations of YM796. As the YM796 concentration increased, however, CL(int,all) fell markedly approaching CL(int).
conclusionsWhile, at low concentrations of YM796, CL(int,all) was predominantly affected by membrane permeability clearance, at high concentrations it was completely rate-determined by the intrinsic metabolic clearance because of the marked reduction in CL(int) resulting from the saturation of YM796 metabolism.
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