EFFECT OF LIVER INTOXICATION BY CARBON-TETRACHLORIDE ON HEPATIC LOCALDISPOSITION 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 s erum albumin (BSA) as a reference substance was evaluated by single-pa ss bolus input method in the isolated perfused rat liver, Oxacillin an d BSA were introduced into the liver from the portal vein, and the out flow concentration-time profiles of oxacillin and BSA from the rat liv er 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 8 0%, with an increase in liver intoxication by CCl4; whereas F-H of BSA was naturally 100%. Mean transit time ($) over bar t(H) of oxacillin increased from 6 to 12 sec, with an increase in liver intoxication; wh ereas ($) over bar t(H), of BSA increased from 7 to 10 sec, The relati ve variance sigma(2)/($) over bar t(H)(2) of oxacillin increased from 0.2 to 0.7, with an increase in liver intoxication; whereas sigma(2)/( $) over bar t(H)(2) of BSA took the value of similar to 0.4, independe nt of liver damage, In the relationship between the dispersion model a nd moments, it was shown that the blood space V-B, increased from 15 t o 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 w ith the increase in liver damage, and the extent of eddy mixing was pr edicted to be unaffected by liver damage, The intensive increases in ( $) over bar t(H) and sigma(2)/($) over bar t(H)(2) Of oxacillin with t he liver intoxication by CCl4 were explained by increases in the exten t of distribution and nonequilibrium distribution, respectively, In co nclusion, the hepatic blood space increased, the elimination of oxacil lin decreased, and the distribution of oxacillin into the hepatic tiss ues increased with CCl4 intoxication, The extent of dispersion (eddy m ixing) in the blood space was not affected by CCl4 intoxication.