The impaired disposition of probe drugs is due to both liver and kidney dysfunctions in CCl(4)-model rats

The carbon tetrachloride (CCl(4))-treated model involving mature Sprague-Dawley rats has been historically relied upon to study liver injury and regeneration and to test drug efficacy and disposition. However, there few studies about phase II metabolic enzymes changes in CCl(4)-model rats. The metabolic and excretion tests of phenacetin and acetaminophen (APAP), and the mRNA test of cytochrome P4501A2 (CYP1A2) and phase II metabolic enzymes [sulfotransferase 1A1 (SULT1A1) and UDP-glucuronosyltransferase 1A6 (UGT1A6)] were studied in model rats after CCl(4) pretreatment. The result showed that the function and structure of liver and kidney was impaired by CCl(4) pretreatment, and a significant difference has been observed in the mRNA content of CYP1A2 (p<0.01) in model group, but there was no significant difference on the mRNA content of SULT1A1 and UGT1A6 in both groups. Compared to the control group, a significant higher content of phenacetin (p<0.01) and sulfate-APAP (AS, p<0.01) was observed in the metabolic tests of phenacetin and APAP. Statistically significant differences in cumulative urinary excretion levels of APAP, AG and AS for CCl(4) model rats were observed also. We have shown that impaired disposition of probe drugs in this model was due to both liver and kidney dysfunction in CCl(4)-model rats and we should consider the development of a new liver damage model without renal impairment.