title: Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine.
abstract: Selective deuterium substitution as a means of ameliorating clinically relevant pharmacokinetic drug interactions is demonstrated in this study. Carbon-deuterium bonds are more stable than corresponding carbon-hydrogen bonds. Using a precision deuteration platform, the two hydrogen atoms at the methylenedioxy carbon of paroxetine were substituted with deuterium. The new chemical entity, CTP-347 [(3S,4R)-3-((2,2-dideuterobenzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine], demonstrated similar selectivity for the serotonin receptor, as well as similar neurotransmitter uptake inhibition in an in vitro rat synaptosome model, as unmodified paroxetine. However, human liver microsomes cleared CTP-347 faster than paroxetine as a result of decreased inactivation of CYP2D6. In phase 1 studies, CTP-347 was metabolized more rapidly in humans and exhibited a lower pharmacokinetic accumulation index than paroxetine. These alterations in the metabolism profile resulted in significantly reduced drug-drug interactions between CTP-347 and two other CYP2D6-metabolized drugs: tamoxifen (in vitro) and dextromethorphan (in humans). Our results show that precision deuteration can improve the metabolism profiles of existing pharmacotherapies without affecting their intrinsic pharmacologies.
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts vuttamsingh@concertpharma.com.
authors.forename: Vinita
authors.initials: V
authors.lastname: Uttamsingh
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Gallegos
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts.
authors.forename: Julie F
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Harbeson
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Bridson
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts.
authors.forename: Changfu
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts.
authors.forename: David S
authors.initials: DS
authors.lastname: Wells
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Graham
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Zelle
authors.affiliation: Concert Pharmaceuticals, Inc., Lexington, Massachusetts.
authors.forename: Roger
authors.initials: R
authors.lastname: Tung
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D003903:Deuterium; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D008862:Microsomes, Liver / Q000378:metabolism; D017374:Paroxetine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism
chemical_list: D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003903:Deuterium; D017374:Paroxetine; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013629:Tamoxifen