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Vol. 293, Issue 3, 761-770, June 2000

Computational Model of Intracellular Pharmacokinetics of Paclitaxel1

Hyo-Jeong Kuh2, Seong Hoon Jang, M. Guillaume Wientjes and Jessie L.-S. Au

College of Pharmacy, Ohio State University, Columbus, Ohio

The intracellular pharmacokinetics of paclitaxel is closely related to its pharmacodynamics. Although drug transport across the cell membrane and extracellular and intracellular drug binding have been shown to affect intracellular drug accumulation, their quantitative relationship is unknown. This study was designed to establish a mathematical model for computing the intracellular paclitaxel pharmacokinetics. As a starting point, the model assumes drug transport into and out of cells via passive diffusion. Experimental data on the intracellular pharmacokinetics of [3H]paclitaxel were obtained using monolayer cultures of human breast MCF7 tumor cells, which have negligible expression of the mdr1 P-glycoprotein. The results indicate that, in addition to drug binding and microtubule concentration, changes in cell number due to cell growth and drug effects also affected intracellular drug accumulation. A kinetic model was developed to describe several concomitant processes: 1) saturable drug binding to extracellular proteins, 2) saturable and nonsaturable drug binding to intracellular components, 3) time- and concentration-dependent drug depletion from culture medium, 4) cell density-dependent drug accumulation, and 5) time- and drug concentration-dependent enhancement of tubulin concentration. The model was validated by the close prediction (<7% deviation) of the effects of extracellular-to-intracellular concentration gradient and cell density on the kinetics of drug accumulation and efflux. This model was used to predict the effects of changing several parameters (number and binding affinity of intracellular binding sites, free fraction, and concentration of drug in extracellular fluid) on intracellular drug accumulation. In conclusion, the computational model of intracellular paclitaxel pharmacokinetics provides the means to predict drug concentration in cells.

1 This work was partially supported by research Grants R37CA49816 and R01CA63363 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Dr. Kuh was partially supported by a Presidential Fellowship awarded by the Ohio State University.

2 Current address: Catholic Research Institutes of Medical Science, Catholic University of Korea, 505 Banpo-dong, Seocho-ku Seoul 137-701, Korea.

0022-3565/00/2933-0761$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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