PHYSIOLOGICALLY-BASED PHARMACOKINETIC PHARMACODYNAMIC MODELING OF THETOXICOLOGIC INTERACTION BETWEEN CARBON-TETRACHLORIDE AND KEPONE/

Carbon tetrachloride (CCl4) lethality in Sprague-Dawley rats is greatl y amplified by pretreatment of Kepone dro-1,3,2-metheno-2H-cyclobuta[c d]pentalen-2-one). The increase in lethality was attributed to the obs truction of liver regenerative processes. These processes are essentia l for restoring the liver to its full functional capacity following in jury by CCl4. Based on the available mechanistic information on Kepone /CCl4 interaction, a physiologically based pharmacokinetic/pharmacodyn amic (PBPK/PD) model was constructed where the following effects of Ke pone on CCl4 toxicity are incorporated: (1) inhibition of mitosis, (2) reduction of repair mechanism of hepatocellular injury (3) suppressio n of phagocytosis. The PBPK/PD model provided computer simulation cons istent with previously published time-course results of hepatotoxicity (i.e., pyknotic, injured and mitotic cells) of CCl4 with or without K epone. As a further verification of this model, the computer simulatio ns were also consistent with exhalation kinetic data for rats injected with different intraperitoneal (i.p.) doses of CCl4 in our laboratory . Subsequently, the PBPK/PD model, coupled with Monte Carlo simulation , was used to predict lethalities of rats treated with CCl4 alone and CCl4 in combination with Kepone. The experimental lethality studies pe rformed in our laboratories were as follows. Sprague-Dawley rats were given either control diet or diet containing 10 ppm Kepone for 15 days , On day 16, rats in the Kepone treated group were given i.p. doses of 0, 10, 50, and 100 mu l/kg CCl4 (n = 9) while control rats were expos ed to 0, 100: 1000, 3000, and 6000 mu l/kg CCl4 (n = 9), Lethality was observed at the 1000 (1/9), 3000 (4/9), and 6000 (8/9) mu l/kg doses for the control group and at the 50 (4/9) and 100 (8/9) mu l/kg for th e treated group. Based on Monte Carlo simulation, which was used to ru n electronically 1000 lethality experiments for each dosing situation, the LD(50) estimates for CCl4 toxicity with and without Kepone pretre atment were 47 and 2890 mu l/kg, respectively, Monte Carlo simulation coupled with the PBPK/PD model produced lethality rates which were not significantly different from the observed mortality, with the excepti on of CCl4 at very high doses (e.g., 6000 mu l/kg, p = 0.014), Deviati on at very high doses of the predicted mortality from the observed may be attributed to extrahepatic systemic toxicities of CCl4, or solvent effects on tissues at high concentrations, which were not presently i ncluded in the model, Our modeling and experimental results verified t he earlier findings of Mehendale (1990) for the 67-fold amplification of CCl4 lethality in the presence of Kepone. However, much of this amp lification of CCl4 lethality with Kepone pretreatment was probably due to pharmacokinetic factors, because when target tissue dose (i.e., mo del estimated amount of CCl4 metabolites) was used to evaluate lethali ty, this amplification was reduced to 4-fold.