This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McKillop, D. Articles by Stephens, T. C. Search for Related Content PubMed PubMed Citation Articles by McKillop, D. Articles by Stephens, T. C.

¹ AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom; ² Inveresk Research, Tranent, United Kingdom; and ³ Oncodesign, Dijon, France

Requests for reprints: David McKillop, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. Phone: 01625-515939; Fax: 01625-516962. E-mail: david.mckillop{at}astrazeneca.com

The relative distribution of gefitinib-related material in nude mice bearing s.c. human tumor xenografts and in an orthotopic rat lung tumor model was investigated following oral administration (50 mg/kg) of [¹⁴C]-gefitinib. Selected tissue samples were monitored for radioactivity by liquid scintillation counting, whereas plasma and tumor extracts were assayed for gefitinib and its major metabolites (M523595 and M537194) by high-performance liquid chromatography with tandem mass spectrometric detection. Tissue distribution was also determined by whole body autoradiography. Gefitinib was extensively distributed into the tissues of tumor-bearing mice and unchanged gefitinib was shown to account for most of the tumor radioactivity. Concentrations of gefitinib in mouse s.c. tumor xenografts were similar to skin concentrations and substantially greater (up to 12-fold based on area under the concentration-time curve) than plasma. Concentrations of gefitinib-related material in an orthotopic rat lung tumor were similar to those in healthy lung tissue and were much higher than corresponding blood levels. Following treatment of breast cancer patients with oral gefitinib (Iressa) 250 mg/d for 14 days, gefitinib concentrations (mean, 7.5 µg/g, 16.7 µmol/L) in breast tumor tissue were 42 times higher than plasma, confirming the preferential distribution of gefitinib from blood into tumor tissue in the clinical situation. These gefitinib tumor concentrations are considerably higher than those reportedly required in vitro to achieve complete inhibition of epidermal growth factor receptor autophosphorylation in both epidermal growth factor receptor mutant (0.2 µmol/L) and wild-type cells (2 µmol/L).

Key Words: Gefitinib • tumor concentrations • pharmacokinetics

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Iressa is a trademark of the AstraZeneca group of companies.

⁴ Unpublished data.

Received 12/ 8/04; revised 1/24/05; accepted 2/ 7/05.