Circulatory transport and capillary-tissue exchange as determinants of the distribution kinetics of inulin and antipyrine in dog

Michael Weiss*, Tom C Krejcie, Michael J Avram

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

A pharmacokinetic model was developed to estimate physiologically meaningful parameters of distribution kinetics from plasma concentration-time data. The model is based on simultaneously measured disposition curves of drug and vascular marker. Employing residence time distribution theory, a recirculatory model with two subsystems, the pulmonary and systemic circulation, was constructed. In addition to intravascular mixing, the axially distributed model of the systemic circulation accounts for transcapillary transport of solutes, quantified by permeability-surface area product (PS) and diffusional equilibration time. Parameters of ICG, inulin, and antipyrine were estimated from disposition data obtained in awake dogs under control conditions and during an isoproterenol infusion or moderate hypovolemia. Results suggest that distribution kinetics is (1) governed by extravascular diffusion and (2) its dependency on cardiac output decreases with increasing diffusional resistance. Hemorrhage decreased the effective PS of inulin. In conclusion, this novel mechanistic model effectively described both the permeability-limited distribution of inulin into interstitial fluid and the flow-limited distribution of antipyrine into total body water and might be useful for other drugs.

Original languageEnglish (US)
Pages (from-to)913-926
Number of pages14
JournalJournal of Pharmaceutical Sciences
Volume96
Issue number4
DOIs
StatePublished - Jan 1 2007

Keywords

  • Blood flow
  • Computational ADME
  • Diffusion
  • Distributed model
  • Distribution
  • Mathematical model
  • Nonlinear regression
  • Permeability
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmaceutical Science

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