Kondo T, Yoshida K, Yoshimura Y, Tanayama S
Drug Analysis and Pharmacokinetics Research Laboratories, Takeda Chemical Industries Ltd., Osaka, Japan.
Biopharm Drug Dispos. 1995 Dec;16(9):755-73. doi: 10.1002/bdd.2510160906.
The enantioselective pharmacokinetics of a new anxiolytic, pazinaclone (DN-2327), and its active metabolite, M-II, were studied in animals. In rats and dogs given racemic pazinaclone intravenously, the total clearance and volume of distribution of (S)-pazinaclone were lower than those of (R)-pazinaclone, whereas the opposite results were obtained in monkeys. The differences in disposition were consistent with enantioselective protein binding, where the unbound fraction was greater for (R)-pazinaclone than that for the (S)-enantiomer in rats and dogs; the reverse was noted in monkeys. Lower clearance and distribution for (S)-pazinaclone in rats and dogs, and for the (R)-enantiomer in monkeys, resulted in comparable plasma profiles for the pazinaclone enantiomers and thereby those of the corresponding enantiomers of M-II. The unbound clearance (CLu) of (S)-pazinaclone was, however, greater than that of the antipode in rats and dogs and the CLu of each enantiomer was similar in monkeys. Thus, enantioselectivity in the kinetics of (S)- and (R)-pazinaclone appears to reside largely in plasma binding differences and is unrelated to variations in intrinsic clearance. The first-pass metabolism of (S)- and (R)-pazinaclone on oral administration of the racemate was enantioselective, with respective bioavailabilities of 1.7 and 0.8% in rats, 10.4 and 1.9% in dogs, and 0 and 11.4% in monkeys. Therefore, the enantioselectivity was more pronounced after oral dosing.
研究了一种新型抗焦虑药帕齐克隆（DN - 2327）及其活性代谢物M - II在动物体内的对映体选择性药代动力学。给大鼠和狗静脉注射外消旋帕齐克隆后，（S）-帕齐克隆的总清除率和分布容积低于（R）-帕齐克隆，而在猴子中得到的结果则相反。处置差异与对映体选择性蛋白结合一致，在大鼠和狗中，（R）-帕齐克隆的未结合部分大于（S）-对映体；在猴子中则相反。大鼠和狗中（S）-帕齐克隆以及猴子中（R）-对映体的清除率和分布较低，导致帕齐克隆对映体以及相应的M - II对映体的血浆浓度曲线相当。然而，（S）-帕齐克隆的未结合清除率（CLu）在大鼠和狗中大于其对映体，并且每种对映体的CLu在猴子中相似。因此，（S）-和（R）-帕齐克隆动力学中的对映体选择性似乎主要在于血浆结合差异，与内在清除率的变化无关。外消旋体口服给药后，（S）-和（R）-帕齐克隆的首过代谢具有对映体选择性，在大鼠中的生物利用度分别为1.7%和0.8%，在狗中为10.4%和1.9%，在猴子中为0和11.4%。因此，口服给药后对映体选择性更为明显。
