title: Effect of Chirality on Common in Vitro Experiments: An Enantiomeric Pair Analysis.
abstract: This analysis elucidates the impact of small molecule architecture on common in vitro ADME assays. In vitro parameters considered in this analysis included Caco-2 permeability/efflux, CYP3A4 inhibition, hERG inhibition, and rat microsomal extraction ratio (ER). The statistical significance and practical meaningfulness of chirality were determined by comparison of the distribution of enantiomers with the experimental variation distribution observed from duplicate measurements. Statistical tools were applied to characterize the role of molecular architecture on the outcome of a given in vitro assay. We found that CYP3A4 inhibition, hERG inhibition, Caco-2 permeability, and efflux are unlikely to be modulated by chirality. However, rat microsomal ER provides a statistically significant, and quantitatively meaningful, chance of being influenced by chirality.
authors.affiliation: †Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Bagdanoff
authors.affiliation: ‡Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton Street, Building 4, Emeryville, California 94608, United States.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: ‡Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton Street, Building 4, Emeryville, California 94608, United States.
authors.forename: Gavin
authors.initials: G
authors.lastname: Dollinger
authors.affiliation: ‡Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton Street, Building 4, Emeryville, California 94608, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Martin
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010599:Pharmacokinetics; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D007521:Isocitrate Dehydrogenase; D051544:Cytochrome P-450 CYP3A