Non-linear elimination and protein binding of probenecid.

Six healthy volunteers were given probenecid 0.5, 1 and 2 g p.o. and 0.5 g i.v. The protein binding of probenecid at different concentrations in human plasma was estimated by equilibrium dialysis. The free fraction was found to increase nonlinearly with increasing total probenecid concentration, up to a maximum free fraction of 26%. The plasma concentration-time data after the oral doses were described by a one-compartment open model with first-order absorption and Michaelis-Menten elimination. The mean absorption rate constant 0.0072 min-1 was dose-independent, and the maximal rate of elimination (mean 1429 micrograms/min) did not differ between doses whether calculated from the total or free concentrations. The Michaelis-Menten constant constant decreased significantly from 67.1 to 55.5 micrograms/ml as the dose increased from 1 g to 2 g, while the unbound Michaelis-Menten constant remained unchanged. The elimination of probenecid after the 0.5 g dose was in the linear region of the Michaelis-Menten elimination when calculated from the total and the free concentrations. The volume of distribution increased only slightly from 9.5 to 11.41 as the dose increased from 0.5 to 2 g, but the unbound volume of distribution decreased significantly from 164 to 99 1. Absorption was complete and was independent of the dose administered.