TY - JOUR T1 - Altering Metabolic Profiles of Drugs by Precision Deuteration: Reducing Mechanism-Based Inhibition of CYP2D6 by Paroxetine JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 43 LP - 54 DO - 10.1124/jpet.115.223768 VL - 354 IS - 1 AU - Vinita Uttamsingh AU - Richard Gallegos AU - Julie F. Liu AU - Scott L. Harbeson AU - Gary W. Bridson AU - Changfu Cheng AU - David S. Wells AU - Philip B. Graham AU - Robert Zelle AU - Roger Tung Y1 - 2015/07/01 UR - http://jpet.aspetjournals.org/content/354/1/43.abstract N2 - 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. ER -