Chemotherapy in a pregnant rat model. 2.5-fluorouracil: nonlinear kinetics and placental transfer

As more women postpone childbearing into their later reproductive years (M. A. Adams, G. P. Oakley, and J. S. Marks, J. Amer. Med. Assoc. 247, 493, 1982), the incidence of cancer in pregnancy is likely to increase. Information regarding the placental transfer and pharmacokinetics of antineoplastic agents is limited. The purpose of this study was to determine the kinetics of 5-fluorouracil, a fluorinated pyrimidine with known nonlinear kinetics (J. M. Collins, R. L. Dedrick, F. G. King, et al., Clin. Pharmacol. Ther. 28, 235, 1980) in a pregnant rat model and compare maternal and fetal disposition. A significant amount of 5-fluorouracil crosses the placenta and the relative fetal exposure increases in a dose-dependent fashion. In the pregnant rat model, 5-FU exhibited nonlinear pharmacokinetics as reflected by an increasing half-life, and a greater than proportional increase in the area under the concentration-time curve (AUC) with increasing dose. Fetal saturation of elimination occurred at a lower dose than in the maternal compartment. The significance of these findings to observed embryotoxicity is discussed in a pharmacodynamic model relating the pharmacokinetic behavior of a drug to its embryotoxic effects.