The Pharmacokinetics of the Interstitial Space in Humans

Overview

Journal BMC Clin Pharmacol

Publisher Biomed Central

Specialty Pharmacology

Date 2003 Aug 2

PMID 12890292

Citations 40

Authors

David G Levitt

Affiliations

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Abstract

Background: The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes.

Methods: The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphine-6-glucuronide, morphine-3-glucuronide, inulin and beta-lactam antibiotics with a range of protein binding (amoxicillin, piperacillin, cefatrizine, ceforanide, flucloxacillin, dicloxacillin). A PBPK data set was developed for extracellular solutes based on the literature for interstitial organ volumes. The program PKQuest was used to generate the PBPK model predictions. The pharmacokinetics of the protein (albumin) bound beta-lactam antibiotics were characterized by two parameters: 1) the free fraction of the solute in plasma; 2) the interstitial albumin concentration. A new approach to estimating the capillary permeability is described, based on the pharmacokinetics of the highly protein bound antibiotics.

Results: About 42% of the total body water is extracellular. There is a large variation in the organ distribution of this water - varying from about 13% of total tissue water for skeletal muscle, up to 70% for skin and connective tissue. The weakly bound antibiotics have flow limited capillary-tissue exchange kinetics. The highly protein bound antibiotics have a significant capillary permeability limitation. The experimental pharmacokinetics of the 11 solutes is well described using the new PBPK data set and PKQuest.

Conclusions: Only one adjustable parameter (systemic clearance) is required to completely characterize the PBPK for these extracellular solutes. Knowledge of just this systemic clearance allows one to predict the complete time course of the absolute drug concentrations in the major organs. PKQuest is freely available http://www.pkquest.com.

Citing Articles

Development and application of a simple pharmacokinetic model that quantitatively describes the distribution and elimination of the commonly measured proteins.

Levitt D, Levitt M ADMET DMPK. 2023; 11(1):57-80.

PMID: 36778906 PMC: 9909726. DOI: 10.5599/admet.1570.

Effect of molecular size on interstitial pharmacokinetics and tissue catabolism of antibodies.

Rafidi H, Rajan S, Urban K, Shatz-Binder W, Hui K, Ferl G MAbs. 2022; 14(1):2085535.

PMID: 35867780 PMC: 9311319. DOI: 10.1080/19420862.2022.2085535.

Clinical Pharmacokinetics and Pharmacodynamics of Cefepime.

Pais G, Chang J, Barreto E, Stitt G, Downes K, Alshaer M Clin Pharmacokinet. 2022; 61(7):929-953.

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PKQuest: PBPK modeling of highly lipid soluble and extracellular solutes.

Levitt D ADMET DMPK. 2022; 7(1):60-75.

PMID: 35350744 PMC: 8957251. DOI: 10.5599/admet.579.

Hyperpolarized C MR Spectroscopy Depicts in Vivo Effect of Exercise on Pyruvate Metabolism in Human Skeletal Muscle.

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