NON-LINEAR PHARMACOKINETICS OF THYMIDINE, THYMINE, AND FLUOROURACIL AND THEIR KINETIC INTERACTIONS IN NORMAL DOGS

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (10) , 4587-4595
Abstract
The pharmacokinetics of thymidine (dThd), thymine and fluorouracil (FUra) were investigated over a range of doses in normal dogs. Evidence was obtained to show that the metabolic elimination of these pyrimidines is saturable, resulting in nonlinear pharmacokinetic behavior. dThd and thymine inhibited the catabolism of FUra. Following i.v. infusion to low-.mu.M steady-state plasma levels (Css = 7.6-12 .mu.M), each compound alone demonstrated an elimination half-life (t1/2) from 2-20 min. When Css was increased to near 1000 .mu.M, the elimination of dThd, thymine and FUra was markedly slower and no longer followed 1st-order kinetics. Over the same concentration range, plasma clearance of each compound decreased .apprx. 90%, while urinary clearance was increased in each case. The relantionship between infusion rate and Css was nonlinear. Using equations based on Michaelis-Menten kinetics, in vivo values of Km and Vmax were determined: Km (in .mu.M): dThd, 45.5; thymine, 82.5; FUra, 39.8; Vmax (in .mu.mol/min per kg): dThd, 2.45; thymine, 2.55; FUra, 2.16. When FUra and thymine or FUra and dThd were infused simultaneously following a base-line infusion of FUra alone, the Css of FUra increased in proportion to the plasma level of thymine achieved. Plasma clearance and metabolism decreased markedly in a nonlinear manner with thymine concentration, while there was little effect on the urinary clearance of FUra. Assuming competitive enzymatic inhibition, in vivo Ki values for dThd and thymine effects on FUra metabolism were 24.2 and 17.4 .mu.M, respectively.