单胺氧化酶
细胞色素P450
化学
新陈代谢
药代动力学
联苯
体外
生物化学
药理学
氯基林
单胺类神经递质
胺气处理
单胺氧化酶B
立体化学
微粒体
酶
生物
有机化学
血清素
受体
作者
Aarti Sawant Basak,Wonkyung Byon,Elaine Tseng-Lovering,Carrie Funk,Linda S. Wood,Chang Lin,Marielle Delnomdedieu,Patrick R. Verhoest,Vinod D. Parikh,Loretta M. Cox,Emily Miller,Hongying Gao,R. Scott Obach
出处
期刊:Xenobiotica
[Taylor & Francis]
日期:2013-12-04
卷期号:44 (5): 438-454
被引量:4
标识
DOI:10.3109/00498254.2013.850552
摘要
1. In early discovery stages, 2-methyl-N-(2'-(pyrrolidinyl-1-ylsulfonyl)-[1,1'-biphenyl]-4-yl)propan-1-amine (PBPA) demonstrated monoamine oxidase A (MAO-A) and cytochrome P450 (CYP)-mediated clearance. While human liver microsomes predicted low CL(b) PBPA demonstrated a moderate CL(p)/F in humans. The plasma pharmacokinetic (PK) of PBPA was characterized by unexpected high inter-individual variability. Hence, a retrospective analysis was undertaken to understand the disposition processes of PBPA, by applying in vitro mechanistic tools. 2. The in vitro-to-in vivo of rat CL(b) of PBPA was calculated as similar to that of human, suggesting rat to be a better predictor of a MAO-A/CYP substrate, but not dog or monkey; this is consistent with differences in expression of MAO-A in rat, dog, monkey and human. Fraction metabolized (f(m)) of human MAO A (hMAO-A) (50%), CYP3A4 (8%), CYP3A5 (16%) and CYP2D6 (29%) was determined, in vitro. 3. While the fm of CYP3A5 was <50%, Michaelis-Menten kinetics demonstrated that it was a higher capacity pathway compared with MAO-A, 2D6 and 3A4. This was consistent with strong association of dose-normalized plasma C(max) and area under the plasma concentration time curve (AUC(0-tlast)) of PBPA with CYP3A5 genotype, but not with genotype of CYP2D6. 4. This investigation demonstrates the value of integrating in vitro mechanistic tools to gain comprehensive understanding of disposition properties of drug candidates, in a discovery paradigm and prior to the investment in clinical trials.
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