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.
Keller
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Medical Department, University Hospital Ulm, Germany.
D000818:Animals; D001682:Biological Availability; D005665:Furosemide / Q000378:metabolism* / Q000493:pharmacokinetics*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008956:Models, Chemical; D009404:Nephrotic Syndrome / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D012709:Serum Albumin / Q000172:deficiency / Q000378:metabolism*
D012709:Serum Albumin; D005665:Furosemide