TY - JOUR T1 - Distribution of KAI-9803, a novel δPKC inhibitor, after intravenous administration to rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.040725 SP - dmd.111.040725 AU - Yoshihiro Miyaji AU - Sarah Walter AU - Leon Chen AU - Atsushi Kurihara AU - Tomoko Ishizuka AU - Motoko Saito AU - Kenji Kawai AU - Osamu Okazaki Y1 - 2011/06/28 UR - http://dmd.aspetjournals.org/content/early/2011/06/28/dmd.111.040725.abstract N2 - KAI-9803 is composed of a selective δPKC inhibitor peptide derived from the δV1-1 portion of δPKC (termed "cargo peptide"), conjugated reversibly to the cell penetrating peptide 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 current study, 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 cleared quickly from the systemic circulation. The microautoradiography analysis showed that 14C-KAI-9803 was effectively delivered into a variety of cells, including cardiac myocytes and cardiac endothelial cells within 1 minute after dosing. The tissue distribution of 125I-labeled KAI-9803 was compared to that of 125I-labeled cargo peptide, demonstrating that the distribution of KAI-9803 to tissues such as the liver, kidney and heart was facilitated by the reversible conjugation to TAT4747-57. In an in vitro cardiomyocyte study, the extent of 125I-KAI-9803 internalization was greater at 37°C than that at 4°C, while 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. ER -