Measurement of Fraction Unbound Paclitaxel in Human Plasma
Open accessAbstract
The clinical pharmacokinetic behavior of paclitaxel (Taxol) is distinctly nonlinear, with disproportional increases in systemic exposure with an increase in dose. We have recently shown that Cremophor EL, the formulation vehicle used for i.v. administration of paclitaxel, alters drug distribution as a result of micellar entrapment of paclitaxel, and we speculated that the free drug fraction (fu) is dependent on dose and time-varying concentrations of Cremophor EL in the central plasma compartment. To test this hypothesis, a reproducible equilibrium dialysis method has been developed for the measurement of paclitaxel fu in plasma. Equilibrium dialysis was performed at 37 degrees C in a humidified atmosphere of 5% CO(2) using 2.0-ml polypropylene test tubes. Experiments were carried out with 260-microliter aliquots of plasma containing a tracer amount of [G-(3)H]paclitaxel with high-specific activity against an equal volume of 0.01 M phosphate buffer (pH 7.4). Drug concentrations were measured by both reversed-phase HPLC and liquid scintillation counting. Using this method, fu has been measured in three patients receiving three consecutive 3-weekly courses of paclitaxel at dose levels of 135, 175, and 225 mg/m(2) and found to range between 0.036 and 0.079. The method was also used to define concentration-time profiles of unbound drug, estimated from the product of the total plasma concentration and fu.
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Taxane concentrations in the plasma of patients with cancer during chemotherapy reach between 0.1 and 1 μM.
“A compound concentration of at least 5 µM was needed to induce a substantial effect (Fig. 1a,e), whereas taxane concentrations in the plasma of patients with cancer during chemotherapy reach concentrations of between 0.1 and 1 µM (refs. 47,48).”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [48]
The Results and Discussion describe 0.03–1.2 μM as the anticipated paclitaxel concentration range for patient samples, which overlaps the cited 0.1–1 μM range. But those numbers were concentrations tested in blank plasma, not a reported range measured in patients; the study also concerns paclitaxel rather than taxanes generally. No page number is available in our copy. (LLM, conf=0.82)
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References 26 · Cited by 98
Research works printed but not linked: 1
- Shah VP, Midha KK, Dighe S, McGilveray IJ, Skelly JP, Yacobi A, Layloff T, Viswanathan CT, Cook CE, McDowall RD, Pittman KA and Spector S (1991) Analytical methods validation: Bioavailability, bioequivalence and pharmacokinetic studies. Conference report. Eur J Drug Metab Pharmacokinet 16:249 -255.
- Authors
- Brouwer, E., Verweij, J., De Bruijn, P., Loos, W. J., Pillay, M., Buijs, D., & Sparreboom, A.
- Affiliations
- Erasmus MC (NL)
- ORCID
- Sparreboom, Alex
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 28
- Issue
- 10
- Pages
- 1141-1145
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2136662093
- Cited by
- 98
- References
- 26
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 3 · 2017: 5 · 2016: 7 · 2015: 4 · 2014: 2 · 2013: 4 · 2012: 2
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- PubMed
- Topics
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- paclitaxel, unbound fraction, free drug fraction, plasma protein binding, Cremophor EL, nonlinear pharmacokinetics, dose-dependent binding, equilibrium dialysis, drug distribution, concentration-time profiles
- MeSH terms
- Antineoplastic Agents, Phytogenic, Binding, Competitive, Dose-Response Relationship, Drug, Female, Glycerol, Humans, Male, Metabolic Clearance Rate, Middle Aged, Plasma, Paclitaxel
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