دورية أكاديمية
An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016).
العنوان: | An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). |
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المؤلفون: | Polli JW; Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Inc., P.O. Box 13398, Room MAI.A2213, Research Triangle Park, NC 27709, USA. joseph.w.polli@gsk.com, Olson KL, Chism JP, John-Williams LS, Yeager RL, Woodard SM, Otto V, Castellino S, Demby VE |
المصدر: | Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2009 Feb; Vol. 37 (2), pp. 439-42. Date of Electronic Publication: 2008 Dec 04. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics, etc.] Country of Publication: United States NLM ID: 9421550 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-009X (Electronic) Linking ISSN: 00909556 NLM ISO Abbreviation: Drug Metab Dispos Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.] |
مواضيع طبية MeSH: | ATP-Binding Cassette Transporters/*metabolism , Biological Transport/*drug effects , Blood-Brain Barrier/*drug effects , Brain/*drug effects , Central Nervous System/*drug effects , Quinazolines/*pharmacology, ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects ; ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology ; ATP-Binding Cassette Transporters/genetics ; Animals ; Antineoplastic Agents/therapeutic use ; Area Under Curve ; Biological Transport/physiology ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Central Nervous System/metabolism ; Cricetinae ; Disease Models, Animal ; Drug Synergism ; Female ; Humans ; Lapatinib ; Male ; Mice ; Mice, Knockout ; Protein Kinase Inhibitors/pharmacology ; Quinazolines/chemistry ; Receptor, ErbB-2/metabolism ; Tissue Distribution |
مستخلص: | Lapatinib is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing human epidermal receptor 2 (ErbB2). This work investigated the role of P-glycoprotein (Pgp; the protein from the Mdr1a/b gene) and breast cancer resistance protein (Bcrp; the protein from the Bcrp1 gene) in modulating the central nervous system penetration of lapatinib at steady-state conditions in FVBn mice (wild-type), Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)/Bcrp1(-/-) knockout mice. After an intravenous infusion of lapatinib for 24 h to a targeted steady-state plasma concentration of 700 ng/ml (0.3 mg/kg/h) or 7000 ng/ml (3 mg/kg/h), lapatinib brain-to-plasma ratios were approximately 3- to 4-fold higher in Mdr1a/b(-/-) knockout mice (ratio range from 0.09 to 0.16) compared with wild-type mice (ratio range from 0.03 to 0.04). There was no difference in the brain-to-plasma ratio in the Bcrp1(-/-) knockout mice (ratio range from 0.03 to 0.04) compared with wild-type mice. In contrast, Mdr1a/b(-/-)/Bcrp1(-/-) triple knockout mice had a 40-fold higher brain-to-plasma ratio (ratio range from 1.2 to 1.7), suggesting that Pgp and Bcrp work in concert to limit the brain-to-plasma ratio of lapatinib in mice. This finding has important potential consequences for the treatment of brain tumors in breast cancer patients treated with tyrosine kinase inhibitors as well as the basic understanding of ATP binding cassette transporters expressed in the blood-brain barrier on the central nervous system disposition of drugs. |
المشرفين على المادة: | 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1) 0 (ATP-Binding Cassette Transporters) 0 (Antineoplastic Agents) 0 (Protein Kinase Inhibitors) 0 (Quinazolines) 0VUA21238F (Lapatinib) EC 2.7.10.1 (Erbb2 protein, mouse) EC 2.7.10.1 (Receptor, ErbB-2) |
تواريخ الأحداث: | Date Created: 20081206 Date Completed: 20090514 Latest Revision: 20220310 |
رمز التحديث: | 20221213 |
DOI: | 10.1124/dmd.108.024646 |
PMID: | 19056914 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1521-009X |
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DOI: | 10.1124/dmd.108.024646 |