Altered Pharmacokinetics of Paclitaxel in Experimental Hepatic or Renal Failure

Abstract

The aim of this study was to investigate the effect of hepatic or renal insufficiency on the pharmacokinetics of paclitaxel in rats. Rats were treated with carbon tetrachloride (CCl4; 0.5 ml/kg) to induce hepatic failure or were subjected to 5/6 nephrectomy (5/6 Nx) to induce renal failure. Paclitaxel (3 mg/kg) was administered intravenously or intraportally. Testosterone 6beta-hydroxylase activity, which is a marker of CYP3A activity, was measured in rat liver microsomes from CCl4-treated or 5/6 Nx rats. After paclitaxel was administered intravenously, total body clearance was significantly reduced by 73% and 34% relative to each control value in CCl4-treated and 5/6 Nx rats, respectively (control, 1.82+/-0.42 vs. CCl4-treated, 0.49+/-0.11; sham, 1.54+/-0.07 vs. 5/6 Nx, 1.01+/-0.12 L h(-1) kg(-1); mean+/-SE, n = 5 to 6). Testosterone 6beta-hydroxylase activity was reduced by 92% and 59% relative to each control value in rat liver microsomes from CCl4-treated and 5/6 Nx rats, respectively. After the intraportal administration of paclitaxel, apparent clearance was reduced by 85% relative to control value in rats with hepatic failure, while that in rats with renal failure was the same as the reduction in systemic clearance. These results suggested that not only hepatic failure but also renal failure could modify the pharmacokinetics of paclitaxel in vivo.