Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

Toxicology and Applied Pharmacology

Volumn 266, Issue 1, 2013, Pages 86-94

  Diaz, Dolores ^a   Ford, Kevin A ^a   Hartley, Dylan P ^b   Harstad, Eric B ^a   Cain, Gary R ^a   Achilles Poon, Kirsten ^a   Nguyen, Trung ^a   Peng, Jing ^a   Zheng, Zhong ^a   Merchant, Mark ^a   Sutherlin, Daniel P ^a   Gaudino, John J ^b   Kaus, Robert ^b   Lewin Koh, Sock C ^a   Choo, Edna F ^a   Liederer, Bianca M ^a   Dambach, Donna M ^a  

^a GENENTECH INC   (United States)

^b ARRAY BIOPHARMA INC   (United States)

Author keywords

Basic amines; Kinase inhibitor; Lysosomes; Met; Phosphatidylserine; Phospholipidosis; PKa; Vd

Indexed keywords

ENZYME INHIBITOR; GEN 203; UNCLASSIFIED DRUG;

ADVERSE OUTCOME; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE MARROW TOXICITY; CONTROLLED STUDY; DRUG DISTRIBUTION; DRUG SAFETY; DRUG STRUCTURE; DRUG TISSUE LEVEL; ENZYME INHIBITION; LIVER TOXICITY; MOUSE; NONHUMAN; PH; PHYSICAL CHEMISTRY;

ANIMALS; CELL LINE, TUMOR; DOSE-RESPONSE RELATIONSHIP, DRUG; DOWN-REGULATION; FEMALE; HUMANS; HYDROGEN-ION CONCENTRATION; MALE; MICE; MICE, NUDE; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-MET; RANDOM ALLOCATION; TISSUE DISTRIBUTION;

MUS;

EID: 84870227233     PISSN: 0041008X     EISSN: 10960333     Source Type: Journal    
DOI: 10.1016/j.taap.2012.10.026     Document Type: Article

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