PF-4981517

PF-4981517, also named CYP3cide, is a potent, efficient, and specific time-dependent inactivator of human CYP3A4. PF-4981517 is a very useful tool for understanding the relative roles of CYP3A4 versus CYP3A5 and the impact of CYP3A5 genetic polymorphism on a compound's pharmacokinetics. PF-4981517 is a lipophilic compound with a pKa which will render it cationic at physiological pH. Thus, it is possible that if incubate with high concentrations of microsomes, it can nonspecifically partition into microsomal phospholipid, and its apparent potency will be reduced. PF-4981517 should be useful to investigators seeking to delineate the relative contribution of CYP3A4 versus CYP3A5 in the metabolism of compounds cleared by CYP3A.

Reference

Robert L. Walsky, R. Scott Obach, Ruth Hyland, Ping Kang, Sue Zhou, Michael West, Kieran F. Geoghegan, Christopher J. Helal, Gregory S. Walker, Theunis C. Goosen and Michael A. Zientek. Selective Mechanism-Based Inactivation of CYP3A4 by CYP3cide (PF-04981517) and Its Utility as an In Vitro Tool for Delineating the Relative Roles of CYP3A4 versus CYP3A5 in the Metabolism of Drugs. DMD September 2012 vol. 40 no. 9 1686-1697.

Selective mechanism-based inactivation of CYP3A4 by CYP3cide (PF-04981517) and its utility as an in vitro tool for delineating the relative roles of CYP3A4 versus CYP3A5 in the metabolism of drugs.[Pubmed:22645092]

Drug Metab Dispos. 2012 Sep;40(9):1686-97.

CYP3cide (PF-4981517; 1-methyl-3-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-4-[(3S)-3-piperidin-1-yl pyrrolidin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine) is a potent, efficient, and specific time-dependent inactivator of human CYP3A4. When investigating its inhibitory properties, an extreme metabolic inactivation efficiency (k(inact)/K(I)) of 3300 to 3800 ml . min(-)(1) . mumol(-)(1) was observed using human liver microsomes from donors of nonfunctioning CYP3A5 (CYP3A5 *3/*3). This observed efficiency equated to an apparent K(I) between 420 and 480 nM with a maximal inactivation rate (k(inact)) equal to 1.6 min(-)(1). Similar results were achieved with testosterone, another CYP3A substrate, and other sources of the CYP3A4 enzyme. To further illustrate the abilities of CYP3cide, its partition ratio of inactivation was determined with recombinant CYP3A4. These studies produced a partition ratio approaching unity, thus underscoring the inactivation capacity of CYP3cide. When CYP3cide was tested at a concentration and preincubation time to completely inhibit CYP3A4 in a library of genotyped polymorphic CYP3A5 microsomes, the correlation of the remaining midazolam 1'-hydroxylase activity to CYP3A5 abundance was significant (R(2) value equal to 0.51, p value of <0.0001). The work presented here supports these findings by fully characterizing the inhibitory properties and exploring CYP3cide's mechanism of action. To aid the researcher, multiple commercially available sources of CYP3cide were established, and a protocol was developed to quantitatively determine CYP3A4 contribution to the metabolism of an investigational compound. Through the establishment of this protocol and the evidence provided here, we believe that CYP3cide is a very useful tool for understanding the relative roles of CYP3A4 versus CYP3A5 and the impact of CYP3A5 genetic polymorphism on a compound's pharmacokinetics.

Selective CYP3A4 inhibitor,PF-4981517 is a potent and selective inhibitor of CYP3A4 (P450) with IC50 of 0.03 μM, exhibits >500-fold selectivity over CYP3A5 and CYP3A7.

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