Gertrude Belle Elion

Acyclovir kinetics after intravenous infusion.

The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1‐hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (±SEM), determined by radioimmunoassay, were 6.4 ±0.7, 12.1 ±2.3, 14.9 ±2.7, and 33.7 ±7.1 µM. The plasma concentration‐time profiles could be described by a biexponential equation. The half‐life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose‐independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse‐phase high‐performance liquid chromatography revealed the presence of the metabolite 9‐carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.

Metabolism of acyclovir in virus-infected and uninfected cells.

The metabolism of acyclovir to its mono-, di-, and triphosphate derivatives was examined in uninfected and virus-infected cells. The level of phosphorylation of acyclovir was dependent upon virus type, cell line, exogenous drug concentration, and exposure time. Acyclovir phosphorylation was inhibited by exogenously added nucleosides. The order of inhibition was deoxythymidine greater than deoxycytidine greater than guanosine greater than or equal to deoxyguanosine. Acyclovir triphosphate persisted in infected cells after removal of the drug from the medium. The initial half-life of the triphosphate was 1.2 h in the absence of the drug in the medium, but triphosphate levels reached a plateau after 6 h. The presence of low concentrations of the drug in the medium resulted in a longer persistence of the intracellular triphosphate and a higher plateau level.

Uptake, distribution, and anabolism of acyclovir in herpes simplex virus-infected mice.

The uptake, distribution, and anabolism of the nucleoside analog 9-(2-hydroxyethoxymethyl) guanine (acyclovir) were compared in herpes simplex virus-infected and uninfected mice. Analyses of tissue distribution and the concentration of acyclovir after either a single dose or multiple doses failed to reveal significant differences between drug levels in infected and uninfected animals. Extracts of tissues from [8-14C] acyclovir-treated animals were examined by high-performance liquid chromatography to detect the presence of any phosphorylated forms of the drug. The sensitivity of this method did not allow a reproducible demonstration of acyclovir anabolism in herpes simplex virus-infected tissues owing to the low numbers of infected cells per organ.