Elimination of the antiviral drug 5-ethyl-2'-deoxyuridine by the isolated perfused rat liver.
The elimination of the antiviral drug 5-ethyl-2'-deoxyuridine (EdUrd) by the isolated perfused rat liver was investigated. EdUrd (3.9-39 mumol) was injected into the perfusion reservoir and serial samples were collected for HPLC determination of EdUrd and its metabolites 5-ethyluracil (EUra) and 5-(1-hydroxyethyl)uracil (HEUra). At each dosage level, semilogarithmic plots of concentration vs. time showed apparent first order disappearance of EdUrd. However, with increasing dose, there was a progressive increase in EdUrd half-life from 18.9 to 36.4 min and decrease in total clearance from 5.5 to 2.5 ml/min, indicating dose-dependent elimination. Dose dependence was confirmed by the lack of superposition of logarithm concentration/dose vs. time plots obtained with different doses. After EdUrd administration, the concentration of EUra reached a peak value in about 1 hr, and then gradually decreased. The concentration of HEUra, which was initially much lower than that of EUra, increased throughout the experiment and appeared to approach a plateau at 2-3 hr. Biliary excretion of each ethylpyrimidine was negligible. 6-Benzyl-2-thiouracil, a thymidine phosphorylase inhibitor, slowed the disappearance of EdUrd and decreased the peak concentrations of EUra and HEUra. Cimetidine, a cytochrome P-450 inhibitor, had little effect on the rate of EdUrd disappearance, but caused a large increase in the peak EUra concentration and decrease in HeUra concentration. 3-Methylcholanthrene, a cytochrome P-450 inducer, increased the formation of HEUra but had little effect on the rate of EdUrd disappearance. The results indicate that the hepatic elimination of EdUrd is dose-dependent and involves an initial cleavage to EUra, which is then oxidized to HEUra.
Joly
J M
JM
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, KY 40292.
Williams
W M
WM
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D002927:Cimetidine / Q000494:pharmacology; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013889:Thiouracil / Q000031:analogs & derivatives / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives / Q000378:metabolism
D000998:Antiviral Agents; C022811:edoxudin; C073778:5-(1-hydroxyethyl)uracil; C048011:5-ethyluracil; D008748:Methylcholanthrene; D014498:Uracil; D013889:Thiouracil; D002927:Cimetidine; C019269:benzylthiouracil; D003857:Deoxyuridine