A positron emission tomography microdosing study with sertraline in healthy volunteers

作者：Shin Kwang Hee; Kim Kyu pyo; Lim Kyoung Soo; Kim Ji Who; Lee Yun Sang; Yang Bo Yeun; Lee Jae Sung; Jung Jae Min; Yoon Seo Hyun; Jang In Jin; Yu Kyung Sang^*

来源：International Journal of Clinical Pharmacology and Therapeutics, 2012, 50(3): 224-232.

DOI：10.5414/CP201644

• microdosing
• CNS drug
• positron emission tomography
• pharmacokinetics
• sertraline

Objective: This study explored microdosing methods for evaluating the distribution and pharmacokinetics (PK) of a central nervous system (CNS) drug candidate. Methods: We used sertraline as a model drug. In this open-label, one-arm, three-period, multiple-dosing study, 10 healthy male volunteers received 6-day administrations of sertraline at doses of 5, 25 or 50 mg/d in three different periods. Before the first dose of Period 1, and 24 h after the last dose of each period, an intravenous bolus of [C-11]sertraline was injected for positron emission tomography (PET) scanning. After the sixth dose in each period, serial blood samples were collected at scheduled intervals over 48 h; then serum sertraline concentrations were determined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Sertraline was distributed in the brain within 20 min, and it was highly distributed in the putamen, cingulate, and thalamus. Linearity in steady-state C-max and AUC(last) were observed in the 5 - 50 mg dose range. The results suggested that microdosing with PET was a useful method for exploring the blood-brain-barrier penetration and distribution of a candidate CNS drug. Conclusions: This study described a microdosing method that combined PET with LC-MS/MS for determining the brain distribution and PK characteristics of a CNS drug candidate.

• 出版日期2012-3