Performance of a diffusional clearance model for beta-lactam antimicrobial agents as influenced by extravascular protein binding and interstitial fluid kinetics

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Abstract
A physiological model based on diffusional clearance (CLD) of drug between plasma and interstitial fluid (IF) was used to describe the disposition of beta-lactam antimicrobial agents. The CLD represents the movement of drug in and out of physiological spaces and is dependent only on the transfer properties of the drug. Estimates of CLD obtained by fitting model equations to plasma concentration-time data for 11 cephalosporin studies in human subjects fell in a fairly narrow range, with a mean value of 1,604 ml/min. Estimates of the CLD between plasma and blister fluid for three of the cephalosporins were five orders of magnitude smaller than the CLD. These observations are explained in terms of diffusion principles. Computer simulations with this model were used to assess the effect of changes in IF protein binding on antimicrobial distribution. Increases in the bound fraction of drug in IF enhanced the penetration of total (bound and unbound) drug into IF, but had no effect on the amount of unbound, active antimicrobial agent reaching the IF. The time course of unbound drug in IF was altered, however, by changes in IF protein binding. This model may also be used to predict changes in the IF distribution of beta-lactam antimicrobial agents in disease states, particularly those in which the relative distribution of albumin between plasma and IF has been altered.