Preclinical Toxicology Studies with Acyclovir: Acute and Subchronic Tests

Preclinical Toxicology Studies with Acyclovir: Acute and SubchronicTests. Tucker, W.E., Jr., Macklin, A.W., Szot, R.J., Johnston,R.E., Elion, G.B., de Miranda, P. and Szczech, G.M. (1983).Fundam. Appl. Toxicol. 3:573–578. Acyclovir (ACV), a newantiherpes drug, was evaluated for toxicity in a series of acuteand subchronic toxicity tests. Oral LD₅₀ values were greaterthan 10 000 mg/kg in male ICR mice and greater than 20 000 mg/kgin male Long Evans rats. When ACV was given iv, the LD₅₀ was405 mg/kg for male mice and greater than 600 mg/kg for malerats. Additionally, LD₅₀ values for male rats treated sc were1070, 790, 678, and 650 mg/kg in rats that were respectively,3, 10, 28 and 71 days old indicating that very young rats werenot more sensitive to acute toxic effects of ACV. There wereno signs of toxicosis in CD-1 mice given ACV by gavage at doselevels of 50, 150 and 450 mg/kg/day for 1 month. Obstructivenephropathy occurred in rats given 20, 40 and 80 mg/kg/day onceeach day by rapid iv injection for 3 weeks. Both 5 and 10 mg/kg/daywere no effect dose levels. Renal damage caused by precipitationof drug crystals in renal tubules and collecting ducts in ratsgiven ACV by rapid iv injection was readily reversible within2 weeks. Beagle dogs were given doses of 10, 20, 25, 50 and100 mg/kg b.i.d. by rapid iv injection for 1 month. All 8 dogsgiven 100 mg/kg b.i.d. died by the 8th day of treatment; 5 of8 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 werenumerous and mainly resulted from the underlying morphologicaland functional changes associated with hypoplasia of the esophagealand gastrointestinal mucosa, lymphoid tissue, and bone marrow.At the 20 and 25 mg/kg b.i.d. dose levels the kidney was thetarget organ; the principal indications of altered renal functionwere increased water intake and hyposthenuria. The dose levelof 10 mg/kg b.i.d. was a no effect level for Beagle dogs treatediv. Thus, in subchronic experiments, the rapid iv injectionof acyclovir caused precipitation of crystals in the renal tubules,resulting in obstructive nephropathy in rats and dogs. Primarytoxicity occurred only in the dog where high doses of acyclovircaused hypoplasia of certain tissues with rapid cell turnover.