Computational Model of Intracellular Pharmacokinetics of Paclitaxel1
Abstract
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 mdr1P-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.
Footnotes
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Send reprint requests to: Dr. Jessie L.-S. Au, College of Pharmacy, 500 West 12th Ave., Columbus, OH 43210. E-mail: au.1{at}osu.edu
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↵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.
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↵2 Current address: Catholic Research Institutes of Medical Science, Catholic University of Korea, 505 Banpo-dong, Seocho-ku Seoul 137-701, Korea.
- Abbreviations:
- Pgp
- P-glycoprotein
- Ctotal,c and Ctotal,m
- total (i.e., free plus bound) drug concentrations in cells and medium, respectively
- Cfree,c and Cfree,m
- free drug concentrations in cells and medium, respectively
- Vc and Vm
- volumes of cells and medium, respectively
- CLf
- clearance of free drug by passive diffusion
- Bmax,c and Bmax,m
- maximum drug-binding capacity in cells and medium, respectively
- Kd,c and Kd,m
- dissociation constants for drug binding to saturable binding sites in cells and medium, respectively
- NSB
- proportionality constant of nonsaturable binding sites in cells
- Vone cell
- mean volume of a single cell
- ICN
- initial cell number at time 0
- kcell number
- rate constant for changes in cell number
- kBmax,c
- rate constant for increase in Bmax,c
- Bmax,c(t) and Bmax,c,initial
- Bmax,c at time t and 0, respectively
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- Received November 2, 1999.
- Accepted February 15, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
