Preclinical toxicology profile of acyclovir: An overview

Abstract

Numerous and extensive toxicologic studies of acyclovir using animal and in vitro assays indicated a low order of toxicity for this antiviral nucleoside analog. Primary cytotoxic effects occurred only at extremely high drug concentrations in plasma or tissue cultures. This correlates well with the high selectivity of the drug for herpes viruses and its low toxicity for uninfected cells in tissue culture. Secondary toxicity in the form of precipitation of acyclovir crystals in the lower nephron of the kidney occurred after rapid intravenous bolus injection causing transient impairment of renal function in the dog, and obstructive nephropathy in the rat. These secondary effects were related to the relatively low solubility of acyclovir in the urine. Dermal and ophthalmic formulations were well-tolerated. No significant primary irritation nor systemic toxic manifestations were associated with the application of these materials. A test in guinea pigs gave no indication that acyclovir has sensitization potential. Acyclovir had no effect on reproductive processes or prenatal, perinatal, or postnatal development of offspring in studies with rats, rabbits, and mice. Positive results occurred in two of 11 in vitro mutagenicity assays. These involved chromosomal damage at extremely high drug concentrations. In contrast, no evidence of chromosomal damage occurred in three in vivo assays at nontoxic dosage levels and under conditions more relevant to clinical use of the drug. While one of two cell transformation assays gave positive results, no oncogenic potential for acyclovir was indicated by lifetime carcinogenicity bioassays in rats and mice. Numerous in vitro and in vivo assays gave no indication that acyclovir might significantly alter immunologic responses at clinically relevant doses.