Saturable first-pass kinetics, plasma protein binding, and the furosemide intricacies.

An equation for saturable nonlinear first-pass kinetics is presented to discuss some contra-intuitive findings encountered with furosemide bioavailability. The diverging effects on steady-state bioavailability (Fss) are simulated for changes in maximal metabolic capacity (Vm), volume of distribution (Vd), Michaelis constant (Km), steady-state plasma concentration (Css), repetitively administered drug dose (Dss), dosage interval (Tau), liver plasma flow (Ql), absorption rate constant (Ka), and free plasma fraction (fp), where (Cssf = fp Css = const.) and (Kmf = fp Km = const.). [Formula: see text] The present concept is in line with observations indicating that furosemide bioavailability decreases from 60 to 45% in nephrotic syndrome patients whose plasma protein binding is reduced and hepatic clearance increased. These observations and our equation-based simulations show that furosemide must have a first-pass effect. Hepatic extraction of furosemide is not facilitated by albumin, and saturable first-pass kinetics can not be used to explain an albumin paradox.