Sex- and age-related mouse toxicity and disposition of the amino acid antitumor agent, acivicin.

Studies of acivicin [(alpha S,5S)-alpha-amino-3-chloro-2-isoxazoline-5-acetic acid, AT-125] plasma levels in ICR, B6D2F1 and CD2F1 mice after single dose i.p. administration showed that total body clearance of drug by male mice was ca. twice the clearance by females of the same strain. Clearance was also greater in older (22-25 g) than in younger (15-18 g) ICR mice. Testosterone pretreatment increased the clearance of acivicin by ICR female mice to that of males. Sex- and age-related differences in pharmacokinetics were more pronounced than strain differences. Excretion studies showed that 53 to 82% of doses were recovered unchanged in the urine with no significant differences between sexes in urinary recovery. In tissue distribution studies in ICR mice, the tissue/plasma concentration ratios at each sampling time were similar for both sexes in all tissues analyzed except kidney (male range: 7-22; female range: 1.5-2.5) and muscle (male range: 5-9; female range: 0.8-1.4). Testosterone pretreatment of females increased the kidney/plasma concentration ratio of acivicin to that of males. Acivicin was also shown to be more toxic (as indicated by LD50) to female than to male mice of the B6D2F1 and CD2F1 strains, in agreement with previous studies in ICR mice. The disposition data suggest that the sex- and age-dependent toxicity of acivicin in mice is due to differences in pharmacokinetics which, in turn, may be related to renal excretion mechanisms.