Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine.
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Uttamsingh V, Gallegos R, Liu JF, Harbeson SL, Bridson GW, Cheng C, Wells DS, Graham PB, Zelle R, Tung R
Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine.
J Pharmacol Exp Ther. 2015 Jul;354(1):43-54. doi: 10.1124/jpet.115.223768. Epub 2015 May 5.
- PubMed ID
- 25943764 [ View in PubMed]
- 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)p iperidine], 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Paroxetine Cytochrome P450 2D6 Protein Humans UnknownSubstrateInhibitorDetails