Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: In vitro and in cancer patients

Jing Li, Julie Brahmer, Wells Messersmith, Manuel Hidalgo, Sharyn D. Baker

Research output: Contribution to journalArticle

Abstract

Gefitinib exhibits wide inter-subject pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug. Thus it is desirable to determine gefitinib binding in plasma and factors affecting this process. An equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (fu) gefitinib in human plasma. Gefitinib binding in plasma from four different species and isolated protein solutions as well as drug partitioning in human blood cells were investigated. Unbound gefitinib plasma concentrations were measured in 21 cancer patients receiving daily oral gefitinib 250 mg or 500 mg. It was found that gefitinib was extensively bound in human rat mouse and dog plasma with mean fu values of 3.4%, 3.8%, 5.1% and 6.0% respectively. In isolated protein solutions approximately 90% and 78% of gefitinib was bound to human serum albumin (HSA) (40 mg/dL) and alpha1-acid glycoprotein (AAG) (1.4 mg/dL) with binding constants of 1.85 × 104 M-1 and 1.13 × 105 M-1 respectively. In whole blood 2.8% of gefitinib existed as the free drug while 79.4% and 17.8% was bound to plasma proteins and blood cells respectively. In plasma from cancer patients fu at pre-treatment varied 2.4-fold (mean 3.4 ± 0.6%; range 2.2-5.4%) and fu was constant over the 28-days of treatment (P > 0.05). Pre-treatment AAG concentration was negatively correlated with pre-treatment fu (R2 = 0.28, P = 0.01). In conclusion gefitinib is highly protein bound (∼ 97%) in human plasma. Variable AAG concentrations observed in cancer patients may affect gefitinib fu with implications for inter-subject variation in drug toxicity and response.

Original languageEnglish (US)
Pages (from-to)291-297
Number of pages7
JournalInvestigational New Drugs
Volume24
Issue number4
DOIs
StatePublished - Jul 2006

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Plasma Cells
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Blood Proteins
Blood Cells
Neoplasms
Glycoproteins
Pharmaceutical Preparations
Acids
gefitinib
In Vitro Techniques
Proteins
Microdialysis
Therapeutics
Drug-Related Side Effects and Adverse Reactions
Serum Albumin
Toxicology
Dialysis
Pharmacokinetics
Pharmacology

Keywords

  • Gefitinib protein binding alpha1-acid glycoprotein pharmacokinetic cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells : In vitro and in cancer patients. / Li, Jing; Brahmer, Julie; Messersmith, Wells; Hidalgo, Manuel; Baker, Sharyn D.

In: Investigational New Drugs, Vol. 24, No. 4, 07.2006, p. 291-297.

Research output: Contribution to journalArticle

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title = "Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: In vitro and in cancer patients",
abstract = "Gefitinib exhibits wide inter-subject pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug. Thus it is desirable to determine gefitinib binding in plasma and factors affecting this process. An equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (fu) gefitinib in human plasma. Gefitinib binding in plasma from four different species and isolated protein solutions as well as drug partitioning in human blood cells were investigated. Unbound gefitinib plasma concentrations were measured in 21 cancer patients receiving daily oral gefitinib 250 mg or 500 mg. It was found that gefitinib was extensively bound in human rat mouse and dog plasma with mean fu values of 3.4{\%}, 3.8{\%}, 5.1{\%} and 6.0{\%} respectively. In isolated protein solutions approximately 90{\%} and 78{\%} of gefitinib was bound to human serum albumin (HSA) (40 mg/dL) and alpha1-acid glycoprotein (AAG) (1.4 mg/dL) with binding constants of 1.85 × 104 M-1 and 1.13 × 105 M-1 respectively. In whole blood 2.8{\%} of gefitinib existed as the free drug while 79.4{\%} and 17.8{\%} was bound to plasma proteins and blood cells respectively. In plasma from cancer patients fu at pre-treatment varied 2.4-fold (mean 3.4 ± 0.6{\%}; range 2.2-5.4{\%}) and fu was constant over the 28-days of treatment (P > 0.05). Pre-treatment AAG concentration was negatively correlated with pre-treatment fu (R2 = 0.28, P = 0.01). In conclusion gefitinib is highly protein bound (∼ 97{\%}) in human plasma. Variable AAG concentrations observed in cancer patients may affect gefitinib fu with implications for inter-subject variation in drug toxicity and response.",
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AU - Messersmith, Wells

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AU - Baker, Sharyn D.

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