Abstract
Intracellular concentration of paclitaxel is determined by the extracellular drug concentration, the level of the mdr1P-glycoprotein (Pgp), and binding to intracellular proteins including tubulins/microtubules. The present study used a computational method to examine the effects of these factors, singly and in combination, on intracellular paclitaxel pharmacokinetics. The study was performed using our previously described intracellular pharmacokinetic model. The parameters representing Pgp-mediated drug efflux and intracellular drug binding (i.e., number of Pgp and binding sites and binding affinity) were altered systematically and used to generate computer simulations depicting the intracellular paclitaxel pharmacokinetics at clinically relevant extracellular (e.g., plasma) drug concentrations. The simulation results indicate that all four factors played a role in determining the intracellular drug accumulation. The rank order of the importance of these parameters was extracellular drug concentration ≫ intracellular binding capacity > intracellular binding affinity > Pgp expression. The results further showed that omission of one or more of these factors in the experimental design would lead to erroneous conclusions on the importance of other factors, as simultaneous changes in more than one parameter altered the relative importance and offset the effects of other parameters. In summary, results of the present study demonstrate the use of computational modeling to depict the effects of biological parameters such as drug efflux transporters, drug binding sites, and binding affinity on intracellular accumulation and retention of drugs that bind to cellular components.
Footnotes
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↵1 Current Address: Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
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This work was partly supported by Research Grants R37CA49816 and R01CA63363 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
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DOI: 10.1124/jpet.102.044172
- Abbreviations:
- mdr1
- multidrug resistance gene 1
- Pgp
- P-glycoprotein
- Jmax
- maximum efflux rate by Pgp per cell
- Bmax,c
- the number of saturable drug binding sites in cells
- Kd,c
- dissociation constants for drug binding to saturable binding sites in cells
- Received September 13, 2002.
- Accepted November 1, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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