Metabolism and clinical pharmacokinetics of 2-methyl-n-(2′-(pyrrolidinyl-1-ylsulfonyl)-n-[1, 1′-biphenyl]-4-yl)propran-1-amine: insights into monoamine oxidase- and CYP-mediated disposition by integration of in vitro ADME tools. (May 2014)

• Record Type: Journal Article
• Authors: Sawant Basak, Aarti; Byon, Wonkyung; Tseng-Lovering, Elaine; Funk, Carrie; Wood, Linda; Lin, Chang; Delnomdedieu, Marielle; Verhoest, Patrick; Parikh, Vinod; Cox, Loretta M.; Miller, Emily; Gao, Hongying; Obach, Ronald S.
• Is Part Of: Xenobiotica. Volume 44:Number 5(2014:May)
• Page Start: 438
• Page End: 454
• Publication Date: 2014-05
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2013.850552
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. <?ri?>In early discovery stages, 2-methyl-<italic>N-</italic>(2′-(pyrrolidinyl-1-ylsulfonyl)-[1, 1′-biphenyl]-4-yl)propan-1-amine <bold>(</bold>PBPA<bold>)</bold> demonstrated monoamine oxidase A (MAO-A) and cytochrome P450 (CYP)-mediated clearance. While human liver microsomes predicted low CL<sub>b</sub> PBPA demonstrated a moderate CL<sub>p</sub>/<italic>F</italic> 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 <italic>in vitro</italic> mechanistic tools.</p> <p>2. <?ri?>The <italic>in vitro-</italic>to-<italic>in vivo</italic> of rat CL<sub>b</sub> 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 (<italic>f</italic><sub>m</sub>) of human MAO A (<italic>h</italic>MAO-A) (50%), CYP3A4 (8%), CYP3A5 (16%) and CYP2D6 (29%) was determined, <italic>in vitro</italic>.</p> <p>3. <?ri?>While the <italic>f</italic><sub>m</sub> 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 <italic>C</italic><sub>max</sub> and area under the plasma concentration time curve (AUC<sub>0-tlast</sub>) of PBPA with CYP3A5 genotype, but not with genotype of CYP2D6.</p> <p>4. <?ri?>This investigation demonstrates the value of integrating <italic>in vitro</italic> mechanistic tools to gain comprehensive understanding of disposition properties of drug candidates, in a discovery paradigm and prior to the investment in clinical trials.</p> </abstract>