Dose-dependent plasma clearance of MK-826, a carbapenem antibiotic, arising from concentration-dependent plasma protein binding in rats and monkeys

After intravenous administration of MK-826, a new carbapenem antibiotic, th e compound exhibited nonlinear pharmacokinetics in rats and monkeys. In bot h species, time-averaged plasma clearance (based on total concentrations) i ncreased about 5-fold over the 10- to 180-mg/kg dose range. MK-826 was exte nsively plasma protein bound in rat and monkey plasma, and the extent of bi nding was concentration dependent at plasma concentrations achieved after a dministration of these doses. Rosenthal analysis of the plasma protein bind ing indicated that there were two classes of binding sites. The binding cap acity of the primary site was comparable to the plasma albumin concentratio n, which suggested that this primary site consisted of a single site on alb umin. The extent of binding of MK-826 to rat albumin was similar to that in whole plasma. Clearance values based on unbound concentrations appeared in dependent of dose from 10 to 180 mg/kg, which is consistent with saturation of protein binding as the primary cause of the nonlinear pharmacokinetic b ehavior.