• Yoshihiro Miyaji, Sarah Walter, Leon Chen, Atsushi Kurihara, Tomoko Ishizuka, Motoko Saito, Kenji Kawai, and Osamu Okazaki.
• 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
• Drug Metab. Dispos. 2011 Oct 1; 39 (10): 1946-53.

AbstractKAI-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.

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