Prediction of changes in the clinical pharmacokinetics of basic drugs on the basis of octanol-water partition coefficients

Junko Ishizaki, Koichi Yokogawa, Emi Nakashima, Fujio Ichimura

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Abstract

A physiologically based pharmacokinetic model for basic drugs has been established on the basis of octanol-water partition coefficients of the non-ionized, unbound drugs (P(oct)). The parameters for the physiological model in man were estimated from a regression equation obtained for the relationships between the P(oct) and the tissue-plasma partition coefficient, the hepatic intrinsic clearance (CL(int,h)) and the blood-to-plasma concentration ratio in rabbits. The plasma concentrations observed after intravenous administration of ten basic drugs (3.2 mg kg-1) to rabbits agreed with the levels predicted using the physiological model (r = 0.710-0.980). In man, the predicted plasma concentrations of basic drugs were in good agreement with reported values (r = 0.729-0.973), except for diazepam and pentazocine. Variations in plasma and brain-concentration profiles of clomipramine and nitrazepam in various disease states were simulated using the model. We assumed that the changes in unbound fraction of drug in serum (f(p)), CL(int,h) and the hepatic blood flow rate were from 0.25- to 4-fold that of the control and that fat volume changed by 0.2- to 5-fold. With regard to changes in f(p), we predicted that the brain-plasma concentration ratio of clomipramine was 1.5- to 25-fold that of the control 24 h after intravenous administration, although the variations in the plasma concentration-time profiles were less marked. Plasma concentrations predicted for several basic drugs were in good agreement with reported values and this physiological model could be useful for predicting drug-disposition kinetics in man.

Original languageEnglish
Pages (from-to)762-767
Number of pages6
JournalJournal of Pharmacy and Pharmacology
Volume49
Issue number8
DOIs
Publication statusPublished - 1997 Aug

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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