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Nonlinear Pharmacokinetics of Thymidine, Thymine, and Fluorouracil and Their Kinetic Interactions in Normal Dogs¹

Department of Pharmacology, The George Washington University Medical Center, Washington, D. C. 20037

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-µM steady-state plasma levels (C_ss = 7.6 to 12 µM), each compound alone demonstrated an elimination half-life (t) between 2 and 20 min. When C_ss was increased to near 1000 µM, 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 C_ss was nonlinear. Using equations based on Michaelis-Menten kinetics, in vivo values of K_m and V_max were determined: K_m (in µM): dThd, 45.5; thymine, 82.5; FUra, 39.8; V_max (in µmol/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 C_ss 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 K_i values for dThd and thymine effects on FUra metabolism were 24.2 and 17.4 µM, respectively.

¹ This work was supported by Grants CA-22866 and 5-T32-CA-09223 awarded by the National Cancer Institute. From a dissertation presented to the Department of Pharmacology, The Graduate School of Arts and Sciences, The George Washington University (7), in partial fulfillment of the requirements for the Ph.D.

² Present address: Laboratory of Medicinal Chemistry and Pharmacology, Developmental Therapeutics Program, National Cancer Institute, NIH, Bethesda, Md. 20205.

³ To whom requests for reprints should be addressed.

Received 11/22/82. Accepted 7/ 6/83.