Effect of liver intoxication by carbon tetrachloride on hepatic local disposition of oxacillin using moment characteristics as index.

The effect of liver intoxication by carbon tetrachloride (CCl4) 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 FH of oxacillin increased from 50% to 80%, with an increase in liver intoxication by CCl4; whereas FH of BSA was naturally 100%. Mean transit time tH of oxacillin increased from 6 to 12 sec, with an increase in liver intoxication; whereas tH of BSA increased from 7 to 10 sec. The relative variance sigma 2/tH2 of oxacillin increased from 0.2 to 0.7, with an increase in liver intoxication; whereas sigma 2/tH2 of BSA took the value of approximately 0.4, independent of liver damage. In the relationship between the dispersion model and moments, it was shown that the blood space VB increased from 15 to 20%, the index for distribution (1 + k') of oxacillin from 1.0 to 1.5, the efficiency number RN 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 tH and sigma 2/tH2 of oxacillin with the liver intoxication by CCl4 were explained by increases in the extent of distribution and nonequilibrium distribution, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)