Preclinical toxicology studies with acyclovir: Acute and subchronic tests

Abstract

Acyclovir (ACV), a new antiherpes drug, was evaluated for toxicity in a series of acute and subchronic toxicity tests. Oral LD 50 values were greater than 10 000 mg/kg in male ICR mice and greater than 20 000 mg/kg in male Long Evans rats. When ACV was given iv, the LD 50 was 405 mg/kg for male mice and greater than 600 mg/kg for male rats. Additionally, LD 50 values for male rats treated sc were 1070, 790, 678, and 650 mg/kg in rats that were respectively, 3, 10, 28 and 71 days old indicating that very young rats were not more sensitive to acute toxic effects of ACV. There were no signs of toxicosis in CD-1 mice given ACV by gavage at dose levels of 50, 150 and 450 mg/kg/day for 1 month. Obstructive nephropathy occurred in rats given 20, 40 and 80 mg/kg/day once each day by rapid iv injection for 3 weeks. Both 5 and 10 mg/kg/day were no effect dose levels. Renal damage caused by precipitation of drug crystals in renal tubules and collecting ducts in rats given ACV by rapid iv injection was readily reversible within 2 weeks. Beagle dogs were given doses of 10, 20, 25, 50 and 100 mg/kg b.i.d. by rapid iv injection for 1 month. All 8 dogs given 100 mg/kg b.i.d. died by the 8th day of treatment; 5 of 8 dogs given 50 mg/kg b.i.d. died after 21 to 31 days of treatment. At 50 and 100 mg/kg b.i.d. the clinical signs of toxicosis were numerous and mainly resulted from the underlying morphological and functional changes associated with hypoplasia of the esophageal and gastrointestinal mucosa, lymphoid tissue, and bone marrow. At the 20 and 25 mg/kg b.i.d. dose levels the kidney was the target organ; the principal indications of altered renal function were increased water intake and hyposthenuria. The dose level of 10 mg/kg b.i.d. was a no effect level for Beagle dogs treated iv. Thus, in subchronic experiments, the rapid iv injection of acyclovir caused precipitation of crystals in the renal tubules, resulting in obstructive nephropathy in rats and dogs. Primary toxicity occurred only in the dog where high doses of acyclovir caused hypoplasia of certain tissues with rapid cell turnover.