Nonlinear Pharmacokinetics & Capacity Dependent Clearance
Clearance (CL) relates the rate of elimination of a molecule with its concentration in vivo. Many small molecules are cleared by enzymatic (metabolism) and transporter based mechanisms. Consequently, molecules cleared by these mechanisms tend to display Michaelis-Menten (MM) or saturable (capacity dependent) kinetics. When concentrations are much below Km, CL is constant (Vmax/Km), exposures increase linearly with dose. When concentrations are much higher than Km, CL is saturated, exposures increase non-linearly with dose. This behavior can be distinguished when concentration and time are plotted on log-linear scale. This has implications in understanding dose-exposure-response relationships in pharmacology and toxicology.