Computer modeling of the pharmacokinetics of Fluorouracil and thymine and their kinetic interaction in normal dogs.

The kinetic behavior of thymine and 5-fluorouracil has been shown to be non-linear and mediated largely by saturable metabolic processes. In vivo estimates of the Michaelis-Menten parameters Vmax and Km were obtained from constant infusion data in normal dogs using a system of balance equations that equate drug input with total output at steady-state. These estimates were then successfully used to simulate both steady-state and post-infusion plasma concentration-time curves for both compounds over a range of saturating and non-saturating conditions. It has been shown previously that estimates of Vmax and Km obtained from dynamic data can be incorrect if an inappropriate compartmental model is used in the analysis. Determining the Michaelis-Menten parameters at steady-state eliminates this difficulty. Moreover, the use of steady-state derived values to simulate post-infusion data confirms the validity of this technique. The kinetic interaction between thymine and 5-fluorouracil was investigated as a case of competitive metabolic inhibition in vivo by calculating Ki values from data obtained during simultaneous constant infusions of the two compounds. These values were then used in conjunction with a series of differential equations incorporating reciprocal metabolic effects to simulate the effect of thymine on FU plasma concentration.