Kusuhara Hiroyuki, Takashima Tadayuki, Fujii Hisako, Takashima Tsutomu, Tanaka Masaaki, Ishii Akira, Tazawa Shusaku, Takahashi Kazuhiro, Takahashi Kayo, Tokai Hidekichi, Yano Tsuneo, Kataoka Makoto, Inano Akihiro, Yoshida Suguru, Hosoya Takamitsu, Sugiyama Yuichi, Yamashita Shinji, Hojo Taisuke, Watanabe Yasuyoshi
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
Drug Metab Pharmacokinet. 2017 Dec;32(6):293-300. doi: 10.1016/j.dmpk.2017.09.003. Epub 2017 Sep 21.
The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16.8 ± 3.5 mL/min/kg and 18.4 ± 12.2% for TMD-322, respectively. The area under the plasma concentration-time curves of cetrozole and TMD-322 after oral administration was markedly lower than that of anastrozole because of their high hepatic clearance. Two subjects out of six exhibited 4- and 17-fold larger exposure of cetrozole than the others following intravenous and oral administration, respectively. Such variation was not observed for TMD-322 and anastrozole. Extensive metabolism of cetrozole and TMD-322 was observed in the CYP2C19 expression system among the test CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). We report the first clinical investigation of our aromatase inhibitors by a cassette microdose strategy in healthy Japanese subjects. This strategy offers an optional approach for candidate selection as a phase zero study in drug development.
本研究的目的是通过盒式微剂量策略，在健康受试者中研究我们新开发的芳香化酶抑制剂（西曲唑和TMD - 322）的药代动力学。将西曲唑和TMD - 322的混合物（每种药物1.98μg）以交叉方式静脉内或口服给予6名健康志愿者。口服混合物中还包括阿那曲唑（1.98μg）。西曲唑的总体清除率和生物利用度分别为12.1±7.1 mL/min/kg和34.9±32.3%，TMD - 322分别为16.8±3.5 mL/min/kg和18.4±12.2%。由于其高肝清除率，口服给药后西曲唑和TMD - 322的血浆浓度 - 时间曲线下面积明显低于阿那曲唑。6名受试者中有2名在静脉内和口服给药后，西曲唑的暴露量分别比其他受试者大4倍和17倍。TMD - 322和阿那曲唑未观察到这种差异。在测试的CYP同工酶（CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4）中，CYP2C19表达系统中观察到西曲唑和TMD - 322的广泛代谢。我们报告了首次在健康日本受试者中通过盒式微剂量策略对我们的芳香化酶抑制剂进行的临床研究。该策略为药物开发中的零期研究提供了一种可选的候选药物筛选方法。
