Effect of experimental liver damage by CCl4 on the pharmacokinetics of zidovudine in rats

ABSTRACT

The effect of CCL4-induced hepatic damage on the pharmacokinetics of zidovudine [AZT] was investigated, in rats, in three phases. The animals were given AZT in phase I, and the results were considered as the control. In the second phase, the rats were administered an oral dose of ml/kg ccl4 to induce acute liver damage. Chronic liver damage was induced in phase III by SC injection of ccl4 [1 ml/kg] every other day for 4 weeks. Rats were administered AZT as an IP dose of 3mg/kg in the three phases. A sensitive HPLC assay was used to measure AZT serum concentrations. The mean AUC after no, acute, and chronic liver damage were 1.95,2.40, and 2.97 mg.hr/l, respectively [p<0.05]. the mean elimination half-life was significantly longer [p<0.05] in the induced chronic liver damage group [2.21 +/- 1.2 hr] compared with rats with rats with no treatment [0.7 +/- 0.23 hr] or with acute liver damage [1.31 +/- 0.28 hr]. the same trend was observed with MRT and AUMC among animals in different experiments. In addition, CI/F was significantly lower [p<0.01] for for rats in phase III compared with rats in the other phases. Rats with induced chronic liver damage eliminate AZT more slowly than rats with acute liver damage [p<0.05]. the present findings indicate that the rat model could be used tostudy the effect of liver impairment on the pharmacokinetics of AZT; the use of AZT in AIDS patients with hepatic impairmant should be closely monitored