ACCUMULATION KINETICS OF DRUGS WITH NON-LINEAR PLASMA-PROTEIN AND TISSUE BINDING CHARACTERISTICS

The accumulation kinetics of drugs which exhibit concentration-dependent binding to tissues and either linear (constant free fraction) or concentration-dependent (increasing free fraction with increasing drug concentration) binding to plasma proteins were studied by digital computer simulation. Elimination rate is presumably proportional to free drug concentration in plasma and instantaneous equilibration of drug occurs between vascular and nonvascular spaces. Nonlinear binding can yield, under certain conditions, apparently biexponential plasma concentration-time curves which may be misinterpreted as being representative of a linear and biexponential system. Such misinterpretation would cause the following errors in the prediction of drug accumulation and elimination kinetics during and after constant-rate infusion: the time required to reach steady state may be overestimated, and the prominence of the apparent distribution phase after cessation of infusion may be underestimated. Drugs with linear and nonlinear plasma protein binding characteristics differ with respect to the relationship between infusion rate and steady-state concentration. This relationship is linear when plasma protein binding is linear. Steady-state concentration increases less than proportionally with increasing infusion rate if plasma protein binding is drug concentration dependent.