Altered pharmacokinetics of paclitaxel in experimental hepatic or renal failure.
OBJECTIVE
The aim of this study was to investigate the effect of hepatic or renal insufficiency on the pharmacokinetics of paclitaxel in rats.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These results suggested that not only hepatic failure but also renal failure could modify the pharmacokinetics of paclitaxel in vivo.
Jiko
Mari
M
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Yano
Ikuko
I
Okuda
Masahiro
M
Inui
Ken-ichi
K
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D017093:Liver Failure / Q000097:blood* / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008862:Microsomes, Liver / Q000378:metabolism; D017239:Paclitaxel / Q000097:blood* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000097:blood* / Q000139:chemically induced; D013250:Steroid Hydroxylases / Q000378:metabolism
D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D013250:Steroid Hydroxylases; C022657:steroid hormone 6-beta-hydroxylase; D017239:Paclitaxel