Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor.
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 > or = 14 days, gefitinib concentrations (mean, 7.5 microg/g, 16.7 micromol/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 micromol/L) and wild-type cells (2 micromol/L).
McKillop
David
D
AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. david.mckillop@astrazeneca.com
Partridge
Elizabeth A
EA
Kemp
John V
JV
Spence
Mike P
MP
Kendrew
Jane
J
Barnett
Sharon
S
Wood
Phillippa G
PG
Giles
Petrina B
PB
Patterson
Andrew B
AB
Bichat
Francis
F
Guilbaud
Nicolas
N
Stephens
Trevor C
TC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011923:Rats, Nude; D012588:Scintillation Counting; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib