Applicability of the Øie-Tozer model to predict three types of distribution volume (Vd) in humans: Vd in central compartment, Vd at steady state, and Vd at beta phase

Masahiro Yahata, Yuji Ishii, Tetsuya Nakagawa, Takao Watanabe, Izuru Miyawaki

Research output: Contribution to journalArticle

Abstract

This study aimed to investigate the applicability of the Øie-Tozer model to predict human distribution volume (Vd) in the central compartment (V1), Vd at steady state (Vdss), and Vd at beta phase (Vdβ) based on animal Vd. Twenty compounds that have a human V1/Vdss of 0.053–0.66 were selected from the literature. After intravenous administration of the compounds at 0.1 mg/kg to rats, dogs, and monkeys, plasma concentrations were determined, and pharmacokinetic parameters were obtained by one/two-compartmental analyses. The human V1, Vdss, and Vdβ were predicted from animal Vd using the Øie-Tozer model, and the predictability was compared with that using proportionality and simple allometry. The Øie-Tozer model was the most reliable method for the overall prediction of Vd and applicable for accurately predicting human V1, Vdss, and Vdβ (89%, 85%, and 68% of the compounds within a 3-fold error, respectively) when data of monkey for V1 and data of three animal species for Vdss and Vdβ were used. Additionally, the predicted human Vd with the two-compartment model was applicable for predicting pharmacokinetic profiles/parameters in humans after intravenous administration of 18 compounds [except for valproic acid (monophasic elimination profile) and chlorpromazine (deviation: Vdss < V1)]. The prediction was more accurate than that using the predicted Vdss with the one-compartment model (e.g., underestimation of maximum plasma concentrations: 2 vs 8 compounds within a 3-fold error, respectively). In summary, the Øie-Tozer model was applicable for predicting human V1, Vdss, and Vdβ, and their predicted Vd with the two-compartment model can lead to accurate pharmacokinetic prediction of compounds that show biphasic elimination.

Original languageEnglish
Pages (from-to)151-165
Number of pages15
JournalBiopharmaceutics and Drug Disposition
Volume41
Issue number4-5
DOIs
Publication statusPublished - Apr 1 2020

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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