Regional pharmacokinetics of 5-bromo-2'-deoxyuridine and 5-fluorouracil in dogs: hepatic arterial versus portal venous infusions.
The purpose of this study was to determine the effect of route of hepatic administration of drug on the regional pharmacokinetics and systemic exposure of 5-fluorouracil (FUra) and 5-bromo-2-deoxyuridine (BrdUrd). A total of 13 mixed-breed male and female dogs were used in these acute studies. Each dog was administered hepatic arterial and portal venous infusions of a single drug, in a cross-over fashion, at two dose rates for a total of four sequential infusions. BrdUrd was studied at 0.250 and 0.500 micromol/min/kg, and FUra was studied at 0.125 and 0.500 micromol/min/ kg. Each infusion lasted 2 h, at which time steady-state plasma concentrations were obtained (ie., gastroduodenal artery, portal vein, hepatic vein, and femoral artery), perfusion rates in hepatic artery and portal vein were measured, and hepatic extraction (as opposed to extraction across the splanchnic region) was directly assessed. BrdUrd and FUra were found to be highly extracted across the liver (E(H) > or = 0.65) at the regional dose rates studied, resulting in low values for the fraction of drug escaping presystemic hepatic elimination (F(H) < or = 0.35). In addition, the regional kinetics (ie., hepatic extraction, fraction escaping first-pass elimination in the liver, and hepatic clearance) and systemic exposure (i.e., CFA) of FUra and BrdUrd were not significantly different following hepatic arterial versus portal venous infusions of drug. Thus, it appears that regional chemotherapy may be applied to halogenated pyrimidines following hepatic arterial, portal venous, and alternating regional dosing routes with no additional risk of systemic toxicity.
Kuan
H Y
HY
College of Pharmacy, Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor 48109, USA.
Smith
D E
DE
Ensmiger
W D
WD
Knol
J A
JA
DeRemer
S J
SJ
Yang
Z
Z
Stetson
P L
PL
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001973:Bromodeoxyuridine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D011169:Portal Vein; D012039:Regional Blood Flow
D000964:Antimetabolites, Antineoplastic; D001973:Bromodeoxyuridine; D005472:Fluorouracil