Effect of liver intoxication by carbon tetrachloride on hepatic local disposition of oxacillin using moment characteristics as index
Yasui, H.; Yamaoka, K.; Fukuyama, T.; Nakagawa, T.
Drug Metabolism and Disposition the Biological Fate of Chemicals 23(8): 779-785
1995
ISSN/ISBN: 0090-9556 PMID: 7493542 Document Number: 447887
The effect of liver intoxication by carbon tetrachloride (CCl-4) on the hepatic local disposition using oxacillin as a test drug and bovine serum albumin (BSA) as a reference substance was evaluated by single-pass bolus input method in the isolated perfused rat liver. Oxacillin and BSA were introduced into the liver from the portal vein, and the outflow concentration-time profiles of oxacillin and BSA from the rat liver into the hepatic vein were kinetically assessed by moment analysis. Liver damage was monitored by plasma SGOT, plasma SGPT, and bile flow rate. Hepatic recovery ratio F-H of oxacillin increased from 50% to 80%, with an increase in liver intoxication by CCl-4; whereas F-H of BSA was naturally 100%. Mean transit time hivin t-H of oxacillin increased from 6 to 12 sec, with an increase in liver intoxication; whereas hivin t-H of BSA increased from 7 to 10 sec. The relative variance sigma-2/ hivin t-H-2 of oxacillin increased from 0.2 to 0.7, with an increase in liver intoxication; whereas sigma-2/ hivin t-H-2 of BSA took the value of apprx 0.4, independent of liver damage. In the relationship between the dispersion model and moments, it was shown that the blood space V-B increased from 15 to 20%, the index for distribution (1 + k') of oxacillin from 1.0 to 1.5, the efficiency number R-N of oxacillin decreased from 0.7 to 0.3 with the increase in liver damage, and the extent of eddy mixing was predicted to be unaffected by liver damage. The intensive increases in hivin t-H and sigma-2/ hivin t-H-2 of oxacillin with the liver intoxication by CCl-4 were explained by increases in the extent of distribution and nonequilibrium distribution, respectively. In conclusion, the hepatic blood space increased, the elimination of oxacillin decreased, and the distribution of oxacillin into the hepatic tissues increased with CCl-4 intoxication. The extent of dispersion (eddy mixing) in the blood space was not affected by CCl-4 intoxication.