PKQuest: capillary permeability limitation and plasma protein binding – application to human inulin, dicloxacillin and ceftriaxone pharmacokinetics

Abstract

Background: It is generally assumed that the tissue exchange of antibiotics is flow limited (complete equilibration between the capillary and the tissue water). This assumption may not be valid if there is a large amount of plasma protein binding because the effective capillary permeability depends on the product of the intrinsic capillary permeability (PS) and the fraction of solute that is free in the blood (fw B ). PKQuest, a new generic physiologically based pharmacokinetic software routine (PBPK), provides a novel approach to modeling capillary permeability in which the only adjustable parameter is the PS of muscle.

Human physiologically based pharmacokinetic model for propofol

“…This criticism applies particularly to the tissue/blood partition coefficients of the different organs, which are impossible to directly measure in humans. The major goal in the development of PKQuest is to address this criticism by the development of a "standard human" PBPK data set whose values have been refined by application to more than 25 different solutes with a wide range of pharmacokinetic properties [3-6,8]. …”

“…The model parameters (organ blood flow, volume, etc.) are identical to those used in previous applications of PKQuest [3-9]. The connective tissue is divided between two organs: "tendon" with a relatively low blood flow, and "other" with a higher blood flow [8].…”

“…The procedures involved in using PKQuest have been described previously [3-8]. All of the standard human PBPK parameters (blood flows, organ weights, etc) and the equations for, e.g., converting freepl to tissue partition values, are pre-programmed and do not have to be entered.…”

“…The model describes the pharmacokinetics in terms of realistic human parameters, such as the organ blood flow and the tissue/blood partition. The PBPK model is implemented in PKQuest, a new software routine that has now been applied to more than 25 different solutes with a wide range of pharmacokinetic properties [3-9]. …”

PKQuest: volatile solutes – application to enflurane, nitrous oxide, halothane, methoxyflurane and toluene pharmacokinetics

“…This new PBPK has been designed to provide a rigorous mathematical treatment that takes into consideration all the different biochemical and physiological properties that a drug may have, and yet be very simple to use. Other papers in this series have described the application of PKQuest to propranolol, D 2 O, ethanol, inulin and protein bound antibiotics [1-3]. This paper will describe the application of PKQuest to volatile solutes, with particular emphasis on anesthetics.…”