Tissue distribution and metabolism of the tyrosine kinase inhibitor ZD6474 (Zactima) in tumor-bearing nude mice following oral dosing

The Journal of Pharmacology and Experimental Therapeutics
Daniel L GustafsonJoseph A Zirrolli

Abstract

ZD6474 [N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-quinazolin-4-amine; Zactima] is a tyrosine kinase inhibitor with antiangiogenic and antitumor activity currently undergoing human trials for cancer treatment. Pharmacokinetic studies in animal models are an important component in the clinical development of this agent to relate preclinical studies to patient treatment. In the studies presented here, the pharmacokinetics of ZD6474 was determined in plasma and tissues of MCF-7 tumor-bearing nude mice following single p.o. doses at 10, 25, and 50 mg/kg. Plasma area under the curve and Cmax were linear, increasing proportionally with dose. Tissue analysis showed that ZD6474 is extensively distributed to tissues, with liver and lung accumulating concentrations of 212 microg/g (approximately 450 microM) and 161 microg/g (approximately 340 microM), respectively. Tumor levels ranged from 27 to 71 microg/g at Cmax levels across the three dose ranges, and ZD6474 was distributed to all of the tissues in a dose-dependent manner. Analysis of putative ZD6474 metabolites in feces found four, with the N-demethyl-piperidinyl-ZD6474 metabolite being the most prominent but still accounting for less than 2% of the tot...Continue Reading

References

May 1, 1994·Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology·G W JepsonJ M Gearhart
Mar 24, 1995·Science·A Levitzki, A Gazit
Jul 1, 1997·Toxicology and Industrial Health·R P BrownR P Beliles
Jan 20, 2000·Journal of Medicinal Chemistry·L F HennequinC Lambert-van der Brempt
Apr 5, 2001·The New England Journal of Medicine·B J DrukerC L Sawyers
Sep 5, 2002·Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine·Roman SchwarzBasil Künnecke
Sep 14, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Roy S HerbstPatricia Mucci LoRusso
Jul 9, 2003·Breast Cancer Research and Treatment·Carol A SartoriusKathryn B Horwitz
Jan 1, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Denis SoulieresLillian L Siu
Jun 1, 2004·Laboratory Investigation; a Journal of Technical Methods and Pathology·Sue C HeffelfingerDavid Warshawsky
Jun 4, 2004·The New England Journal of Medicine·Herbert HurwitzFairooz Kabbinavar
Dec 30, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kaye J WilliamsStephen R Wedge
May 21, 2005·Annals of Oncology : Official Journal of the European Society for Medical Oncology·S N HoldenH I Hurwitz
Jun 1, 2005·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M P MorelliF Ciardiello
Jun 7, 2005·Journal of Pharmaceutical and Biomedical Analysis·Joseph A ZirrolliDaniel L Gustafson
Aug 3, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Vincenzo DamianoGiampaolo Tortora
Oct 21, 2005·The New England Journal of Medicine·Martine J Piccart-GebhartUNKNOWN Herceptin Adjuvant (HERA) Trial Study Team
Feb 10, 2006·The New England Journal of Medicine·James A BonnerK Kian Ang

❮ Previous
Next ❯

Citations

Mar 17, 2009·European Journal of Nuclear Medicine and Molecular Imaging·Erik SaménSharon Stone-Elander
Mar 1, 2013·European Journal of Drug Metabolism and Pharmacokinetics·C JoveletS Gil
Sep 16, 2008·Molecular Cancer Therapeutics·Erica L Bradshaw-PierceDaniel L Gustafson
Apr 10, 2012·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·C JoveletS Gil
Oct 6, 2009·International Journal of Radiation Oncology, Biology, Physics·Phyllis WachsbergerAdam P Dicker
Aug 13, 2015·Parasites & Vectors·Noemi Cowan, Jennifer Keiser
Apr 28, 2009·Leukemia Research·Hong-Yun JiaWenlin Huang
Nov 17, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Derek W AngusIain J Martin
Jun 18, 2020·Frontiers in Pharmacology·Maria CondelloStefania Meschini
Mar 20, 2013·The Journal of Clinical Endocrinology and Metabolism·Dmytro Starenki, Jong-In Park
Sep 4, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Wenhong RenDina Lev
Oct 31, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Vijaya L DamarajuMichael B Sawyer
Dec 10, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Yuko TaniharaKen-Ichi Inui

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.