title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism , Pfizer Inc., Cambridge, MA , USA.
authors.forename: Aarti
authors.initials: A
authors.lastname: Sawant Basak
authors.forename: Wonkyung
authors.initials: W
authors.lastname: Byon
authors.forename: Elaine
authors.initials: E
authors.lastname: Tseng-Lovering
authors.forename: Carrie
authors.initials: C
authors.lastname: Funk
authors.forename: Linda
authors.initials: L
authors.lastname: Wood
authors.forename: Chang
authors.initials: C
authors.lastname: Lin
authors.forename: Marielle
authors.initials: M
authors.lastname: Delnomdedieu
authors.forename: Patrick
authors.initials: P
authors.lastname: Verhoest
authors.forename: Vinod
authors.initials: V
authors.lastname: Parikh
authors.forename: Loretta M
authors.initials: LM
authors.lastname: Cox
authors.forename: Emily
authors.initials: E
authors.lastname: Miller
authors.forename: Hongying
authors.initials: H
authors.lastname: Gao
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Obach
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D004912:Erythrocytes / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: C568463:2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine; D001713:Biphenyl Compounds; D013449:Sulfonamides; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008995:Monoamine Oxidase