Volume of distribution terms for a drug (ceftriaxone) exhibiting concentration-dependent protein binding. I. Theoretical considerations.
We have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, fp) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both V beta and the model-independent VSS) were inaccurate/invalid; b) V beta based on unbound drug was misleading; c) the model-independent VSS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms (-fp and V-TSS) were introduced which provide additional insight concerning the disposition of this type of drug. The -fp is the area-weighted average fraction unbound in the plasma and V-TSS is the corrected steady state distribution term for total drug levels. The present study indicates that useful distributional and clearance terms can be calculated for this type of drug, provided that the time course of unbound drug as well as total drug can be followed. Moreover, guidelines for their extrapolation to steady state conditions and their correct interpretations are discussed.
D001798:Blood Proteins / Q000378:metabolism*; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000378:metabolism; D002443:Ceftriaxone; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008433:Mathematics; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011485:Protein Binding
D001798:Blood Proteins; D002443:Ceftriaxone; D002439:Cefotaxime