title: Distribution of KAI-9803, a novel δ-protein kinase C inhibitor, after intravenous administration to rats.
abstract: KAI-9803 is composed of a selective δ-protein kinase C (δPKC) inhibitor peptide derived from the δV1-1 portion of δPKC (termed "cargo peptide"), conjugated reversibly to the cell-penetrating peptide 11-amino acid, arginine-rich sequence of the HIV type 1 transactivator protein (TAT₄₇₋₅₇; termed "carrier peptide") via a disulfide bond. KAI-9803 administration at the end of ischemia has been found to reduce cardiac damage caused by ischemia-reperfusion in a rat model of acute myocardial infarction. In the study presented here, we examined the TAT₄₇₋₅₇-mediated distribution of KAI-9803 in rats after a single intravenous bolus administration (1 mg/kg). ¹⁴C-KAI-9803 was rapidly delivered to many tissues, including the heart (1.21 μg eq/g tissue), while being quickly cleared from the systemic circulation. The microautoradiography analysis showed that ¹⁴C-KAI-9803 was effectively delivered into various cells, including cardiac myocytes and cardiac endothelial cells within 1 min after dosing. The tissue distribution of ¹²⁵I-labeled KAI-9803 was compared to that of ¹²⁵I-labeled cargo peptide; this comparison demonstrated that the distribution of KAI-9803 to tissues such as the liver, kidney, and heart was facilitated by the reversible conjugation to TAT₄₇₋₅₇. In an in vitro cardiomyocyte study, the extent of ¹²⁵I-KAI-9803 internalization was greater at 37°C than that at 4°C, whereas the internalization of the ¹²⁵I-cargo peptide at 37°C was not observed, indicating that the uptake of ¹²⁵I-KAI-9803 into the cardiomyocytes was mediated by the TAT₄₇₋₅₇ carrier. Our studies demonstrated that after a single intravenous administration, KAI-9803 can be delivered into the target cells in the liver, kidney, and heart by a TAT₄₇₋₅₇-mediated mechanism.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. miyaji.yoshihiro.kc@daiichisankyo.co.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyaji
authors.forename: Sarah
authors.initials: S
authors.lastname: Walter
authors.forename: Leon
authors.initials: L
authors.lastname: Chen
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurihara
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishizuka
authors.forename: Motoko
authors.initials: M
authors.lastname: Saito
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawai
authors.forename: Osamu
authors.initials: O
authors.lastname: Okazaki
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D057846:Cell-Penetrating Peptides / Q000378:metabolism; D002478:Cells, Cultured; D015696:Gene Products, tat / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D057846:Cell-Penetrating Peptides; D015696:Gene Products, tat; C527142:KAI 9803; D010455:Peptides; D047428:Protein Kinase Inhibitors; D051745:Protein Kinase C-delta