Nonlinear pharmacokinetics of thymidine, thymine, and fluorouracil and their kinetic interactions in normal dogs.

We have investigated the pharmacokinetics of thymidine (dThd), thymine, and fluorouracil (FUra) 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. Additionally, dThd and thymine were shown to inhibit the catabolism of FUra. Following i.v. infusion to low-microM steady-state plasma levels (Css = 7.6 to 12 microM), each compound alone demonstrated an elimination half-life (t1/2) between 2 and 20 min. When Css was increased to near 1000 microM, the elimination of dThd, thymine, and FUra was markedly slower and no longer followed first-order kinetics. Over the same concentration range, plasma clearance of each compound decreased about 90%, while urinary clearance was increased in each case. The relationship 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 microM): dThd, 45.5; thymine, 82.5; FUra, 39.8; Vmax (in mumol/min/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 microM, respectively.