RT Journal Article SR Electronic T1 Kinetics of Drug Metabolism in Rat Liver Slices JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 460 OP 467 VO 25 IS 4 A1 Philip D. Worboys A1 Alan Bradbury A1 J. Brian Houston YR 1997 UL http://dmd.aspetjournals.org/content/25/4/460.abstract AB The time course for distribution of five compounds (caffeine, tolbutamide, phenytoin, ondansetron, and diazepam) was studied in precision-cut rat liver slices. Transport of these compounds differed greatly, with caffeine being distributed rapidly, but not accumulating above the media concentration. Although tolbutamide similarly was not accumulated within the tissue, its uptake rate was slower. The rate of phenytoin, ondansetron, and diazepam distribution (with appropriate corrections for metabolism) was slower still; yet, these drugs were accumulated within the cells of the slice to a concentration ∼15-fold that of the media. Examination of the physicochemical properties of these compounds demonstrated that the extent of accumulation positively correlated with lipophilicity, whereas the rate of uptake was not statistically correlated with log D. The extent of accumulation within the slice was assessed by an apparent volume of distribution parameter (ranging from 26 to 195 μl/slice). Using cell:media partition coefficients determined in hepatocytes and the intra- and extracellular spaces within the slice (as measured with the markers tritiated water and sucrose), it was possible to predict apparent volumes of distribution for each drug in the liver slice. Comparison of observed and predicted apparent volumes of distribution gave ratios of 0.34–1. Intrinsic clearance values for these five drugs are available for slices and cells (slice:cell intrinsic clearance ratios 0.05–0.43; Worboys et al., Drug Metab. Dispos. 24, 676–681, 1996). Drugs that demonstrate low intrinsic clearance ratios also have low apparent volume ratios, thus indicating that reduced drug uptake and clearance in slices, relative to hepatocytes, are interdependent. Both phenomena may be rationalized by the existence of a drug concentration gradient within the slice. At very high drug concentrations, Vmax operates, and the consequence of the gradient is minimal. Therefore, it is possible to speculate upon the fraction of hepatocytes within the slice contributing to clearance by considering Vmaxvalues. For six pathways of metabolism, Vmax in slices averages 35% of the corresponding parameter in isolated hepatocytes. This is most likely due to limited oxygen and compromised metabolic function of the core cells. These distribution phenomena severely complicate the possibility of using a scaling factor based on the theoretical number of slices obtainable from a liver to predictin vivo intrinsic clearance. The American Society for Pharmacology and Experimental Therapeutics