Pharmacokinetics, metabolic activation, and lung toxicity of cyclophosphamide in C57/B16 and ICR mice.
A single intraperitoneal dose (200 mg/kg) of cyclophosphamide (CP) resulted in significantly less injury to the C57/B16 strain than to the ICR strain of mice. Maximal thymidine incorporation into total lung DNA, an indirect index of lung injury, and pulmonary hydroxyproline content, a marker of fibrosis, were 56 +/- 10% and 69 +/- 9 of ICR mice, respectively. Pharmacokinetics and metabolism of [side chain-3H]CP and [ring-14C]CP were assessed in vivo. In addition, covalent binding and the generation of polar metabolites were determined in hepatic and pulmonary microsomes from both strains. Peak levels and half-lives of radioactivity derived from CP in blood were similar in both strains treated with a 200 mg/kg dose. However, area under curve for total radioactivity over 12 hr was significantly lower (60 and 78% of ICR for 3H and 14C, respectively), and systemic clearance significantly higher (168 and 119% of ICR for 3H and 14C, respectively) in the C57 strain. Total radioactivity derived from CP in lung and liver was similar between strains at all time points examined up to 12 hr, but overall covalent binding of radioactivity, assessed as area under the binding curve, was markedly lower to C57 lungs in vivo (58 and 49% of ICR for 3H and 14C, respectively). In contrast, hepatic binding was not significantly different between strains with either label. No significant differences were evident between strains in hepatic or pulmonary microsomal binding in vitro. Polar CP metabolites in ICR lung were significantly higher than C57 at 2 hr in vivo, but no strain differences were evident at other times nor in the microsomal generation of polar metabolites. These results demonstrate significant differences in the pharmacokinetics of CP between C57 and ICR murine strains. NADPH-mediated activation of CP in vitro was similar between strains suggesting that the increased covalent binding of CP to ICR lung tissue in vivo was due to greater exposure to CP or its reactive metabolites. The relative resistance of C57 mice to CP-induced lung fibrosis may also be influenced by intrinsic differences in response of the lung to reactive CP species, or by differences in activation by other metabolic pathways.
Kanekal
S
S
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712-1074.
Fraiser
L
L
Kehrer
J P
JP
D000818:Animals; D001711:Biotransformation; D003520:Cyclophosphamide / Q000493:pharmacokinetics*; D004247:DNA / Q000032:analysis; D004198:Disease Susceptibility; D006909:Hydroxyproline / Q000032:analysis; D007274:Injections, Intraperitoneal; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008861:Microsomes / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D003520:Cyclophosphamide; D004247:DNA; D006909:Hydroxyproline; D013936:Thymidine