DMD Large equally mixed donor pool

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Karlsson, M. O.
Right arrow Articles by Larsson, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Karlsson, M. O.
Right arrow Articles by Larsson, R.

Vol. 27, Issue 10, 1220-1223, October 1999

Pharmacokinetic Models for the Saturable Distribution of Paclitaxel

Mats O. Karlsson, Valeria Molnar, Agneta Freijs, Peter Nygren, Jonas Bergh, and Rolf Larsson

Division of Biopharmaceutics and Pharmacokinetics, Department of Pharmacy, Faculty of Pharmacy, Uppsala University (M.O.K., V.M., A.F.); and Departments of Oncology (P.N., J.B.) and Clinical Pharmacology (R.L.), Faculty of Medicine, Uppsala Akademiska Hospital, Uppsala, Sweden

Paclitaxel pharmacokinetics are nonlinear with saturable metabolism and saturable distribution to the tissues. The saturable distribution has in previous pharmacokinetic modeling been described as a saturable transport process, whereas the present study was undertaken to investigate alternative explanations. Using a sparse sampling scheme (on average 3.3 samples per profile), 101 plasma concentration-time profiles in 22 female patients with metastatic cancer of the breast or ovary were monitored. It was found that the observed data could be equally well described by saturable tissue binding as well as by capacity-limited tissue transport. The data were better described by a model where equilibrium was achieved with drug in the central rather than in the peripheral compartment. Models where the binding was assumed to be an instantaneous or a noninstantaneous process were tried, but the data did not allow resolution between these two possibilities. The value at which the saturable transport was half-maximal was 0.55 µM. The Kd values of the binding models were 0.06 to 0.12 µM. These are close to the values reported as a threshold for drug toxicity of paclitaxel, suggesting a possible connection between the binding sites involved in the pharmacokinetics and the mechanism responsible for the toxicity. For all models, a saturable elimination of paclitaxel was included using the Michaelis-Menten model. Km for the elimination ranged in the different models from 2.5 to 5.6 µM.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Cell Sci.Home page
K. E. Gascoigne and S. S. Taylor
How do anti-mitotic drugs kill cancer cells?
J. Cell Sci., August 1, 2009; 122(15): 2579 - 2585.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. Joerger, A. D.R. Huitema, D. J. Richel, C. Dittrich, N. Pavlidis, E. Briasoulis, J. B. Vermorken, E. Strocchi, A. Martoni, R. Sorio, et al.
Population Pharmacokinetics and Pharmacodynamics of Paclitaxel and Carboplatin in Ovarian Cancer Patients: A Study by the European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms Group and New Drug Development Group
Clin. Cancer Res., November 1, 2007; 13(21): 6410 - 6418.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. Joerger, A. D.R. Huitema, D. H.J.G. van den Bongard, J. H.M. Schellens, and J. H. Beijnen
Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of Paclitaxel in patients with solid tumors.
Clin. Cancer Res., April 1, 2006; 12(7 Pt 1): 2150 - 2157.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
J. Gligorov and J. P. Lotz
Preclinical Pharmacology of the Taxanes: Implications of the Differences
Oncologist, June 2, 2004; 9(suppl_2): 3 - 8.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
C. Ferlini, G. Raspaglio, S. Mozzetti, M. Distefano, F. Filippetti, E. Martinelli, G. Ferrandina, D. Gallo, F. O. Ranelletti, and G. Scambia
Bcl-2 Down-Regulation Is a Novel Mechanism of Paclitaxel Resistance
Mol. Pharmacol., July 1, 2003; 64(1): 51 - 58.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
Ch. van Kesteren, R. A.A. Mathot, E. Raymond, J. P. Armand, Ch. Dittrich, H. Dumez, H. Roche, J. P. Droz, C. Punt, M. Ravic, et al.
Population Pharmacokinetics of the Novel Anticancer Agent E7070 During Four Phase I Studies: Model Building and Validation
J. Clin. Oncol., October 1, 2002; 20(19): 4065 - 4073.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
P. B. Cassidy, P. J. Moos, R. C. Kelly, and F. A. Fitzpatrick
Cyclooxygenase-2 Induction by Paclitaxel, Docetaxel, and Taxane Analogues in Human Monocytes and Murine Macrophages: Structure-Activity Relationships and Their Implications
Clin. Cancer Res., March 1, 2002; 8(3): 846 - 855.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. Henningsson, M. O. Karlsson, L. Vigano, L. Gianni, J. Verweij, and A. Sparreboom
Mechanism-Based Pharmacokinetic Model for Paclitaxel
J. Clin. Oncol., October 15, 2001; 19(20): 4065 - 4073.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
E. Brouwer, J. Verweij, P. De Bruijn, W. J. Loos, M. Pillay, D. Buijs, and A. Sparreboom
Measurement of Fraction Unbound Paclitaxel in Human Plasma
Drug Metab. Dispos., October 1, 2000; 28(10): 1141 - 1145.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.