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.

High-performance liquid chromatographic analysis of 5-ethylpyrimidines and 5-methylpyrimidines in plasma.

A high-performance liquid chromatographic (HPLC) method employing a C18 reversed-phase column, a mobile phase of sodium acetate and methanol, and an ultraviolet detector was developed for the analysis of 5-ethylpyrimidines and 5-methylpyrimidines in plasma. Samples were prepared for HPLC by sequential cation-exchange and anion-exchange column chromatography. Linear standard curves were obtained for samples containing 0.05-50 micrograms/ml 5-ethyl-2'-deoxyuridine and 5-ethyluracil, 0.05-10 micrograms ml 5-(1-hydroxyethyl)uracil, and 0.1-50 micrograms/ml thymidine, thymine and 5-hydroxymethyluracil. Applicability of the method to determination of the kinetics of 5-ethyl-2'-deoxyuridine elimination by the isolated perfused rat liver was demonstrated; clearance of the drug was 1.29 ml/min.

Metabolism of aspirin and procaine in mice pretreated with O-4-nitrophenyl methyl(phenyl)phosphinate or O-4-nitrophenyl diphenylphosphinate.

Concentrations of [carboxyl-14C]procaine in blood of mice were increased threefold for 27 min by exposure to O-4-nitrophenyl diphenylphosphinate 2 hr prior to [carboxyl-14C]procaine injection ip, while there was no effect of O-4-nitrophenyl methyl(phenyl)phosphinate pretreatment. There was no effect of either organophosphinate on the primary hydrolysis of [acetyl-l-14C]aspirin when assessed by the expiration of [14C]carbon dioxide; however, O-4-nitrophenyl diphenylphosphinate pretreatment produced transient increases in blood concentrations of both [carboxyl-14C]aspirin and [carboxyl-14C]salicylic acid following administration of [carboxyl-14C]aspirin. Liver carboxylesterase activity in O-4-nitrophenyl diphenylphosphinate pretreated mice was 11% of control activity. These results indicate the potential for drug interaction with O-4-nitrophenyl diphenylphosphinate but not with O-4-nitrophenyl methyl(phenyl)phosphinate. It appears that liver carboxylesterase activity has a minor role in hydrolysis of aspirin in vivo, but may be more important in procaine metabolism.