PHARMACOKINETICS AND BIOAVAILABILITY OF ACYCLOVIR IN THE DOG

Abstract

Acyclovir [9-(2-hydroxyethoxymethyl)guanine, Zovirax] is a selective antiviral agent with indications for the treatment of the herpes virus group of infections. In a cross-over design study, 3 male beagle dogs were given acyclovir i.v. and p.o. (capsule) at 5, 20 and 50 mg/kg doses. Dogs received acyclovir by gavage at these 3 doses. After i.v. injection, the acyclovir plasma concentration-time profile, determined by radioimmunoassay, exhibited a biexponential decay with a terminal t1/2 of 2.2-3.6 h. Plasma clearance (3.48-5.83 ml/min per kg) approximated the normal glomerular filtration rate in dogs and the Vd.beta. (0.97-1.17 l/kg) indicated distribution of the drug into tissues. Similar kinetic findings were obtained after i.v. administration of [8-14C]acyclovir to dogs. The radioactivity recovered in the urine was 95% of the dose, and 92% of the urinary 14C was identified as acyclovir. The remainder of 14C correspond to minor urinary metabolites. The plasma acyclovir concentration-time curves generated from oral (capsule and gavage) data were fit to a 1-compartment open pharmacokinetic model. The half-life and Vd parameters were similar to those calculated for the i.v. route. Peak plasma drug concentrations were reached within 2 h of dosing. Good oral bioavailability (91 and 80%) was observed after the administration of a capsule at the lower doses (5 and 20 mg/kg, respectively), but bioavailability declined (52%) at the 50 mg/kg dose, indicating the possibility that the gastrointestinal absorption of acyclovir is a saturable process.