Theophylline. Pooled Michaelis-Menten parameters (Vmax and Km) and implications

Abstract

The literature on theophylline is confusing since in the same dose range one article will report linear kinetics while another will report non-linear kinetics. Single dose clearances and lower steady-state clearances of theophylline, recently reported in the literature, were used to estimate pooled Vmax and Km values of the Michaelis-Menten equation for 10 normal subjects. The mean Vmax was 1960 mg/day and the mean Km was 24.1 mg/L. These values were then utilised to: explain another set of different oral clearances following doses of 2 and 6 mg/kg reported in the literature; estimate relative effects of dose rate and type of input on absolute bioavailability; estimate AUC (0-infinity) as a function of single dose over the range 0 to 1500 mg; estimate the average steady-state serum concentration of theophylline (Cssav and steady-state oral clearance (CLsspo) as a function of dose rate in mg/day; illustrate how Michaelis-Menten kinetics alters the apparent first-order elimination rate constant and the half-life estimated from terminal log-linear plots at concentrations appreciably lower than the Km value; and illustrate how Michaelis-Menten kinetics affects the estimation of a zero-order absorption rate constant using the Wagner-Nelson method.