Deuterium in Drug Discovery and Development

Altering Metabolic Profiles of Drugs by Precision Deuteration: Reducing Mechanism-Based Inhibition of CYP2D6 by Paroxetine

“…At a concentration of 1 mM, the deuterated and all-hydrogen molecules were approximately equipotent in their inhibitory interactions with other molecular targets, including the human serotonin, norepinephrine, and dopamine transporters; human muscarinic receptors; and rat L-type calcium channels (Table 1). These results are consistent with previous studies indicating that deuterium substitution had little impact on pharmacologic activity and molecular structure relative to their all-hydrogen analogs (Di Costanzo et al, 2007;Harbeson and Tung, 2011).…”

“…One recent report, for instance, described a phase 1 evaluation of another novel deuterium-containing, controlled-release drug candidate under development for diabetic neuropathy, although the effects of this latter agent on metabolic and pharmacokinetic profiles were not detailed (Braman et al, 2013). Other new agents are being investigated (http://investor.auspexpharma.com/releasedetail.cfm?releaseid5887958; Harbeson and Tung, 2011;Lu et al, 2015). It is important to note that the effects observed in this study (i.e., reduced MBI and a consequent increase in firstpass metabolism) may be quite different from the metabolismrelated effects imparted by deuteration of other drugs.…”

“…The reduced MBI and drug-drug interaction of CTP-347 relative to paroxetine might be beneficial in a variety of clinical settings; however, a range of complicating factors in whole organisms may mask or even reverse the theoretical consequences of drug deuteration (Harbeson and Tung, 2011), and it was therefore of interest to determine whether any effects observed in vitro with the deuterated agent translated into the clinical setting.…”

“…Compounds labeled with deuterium, a nonradioactive isotope of hydrogen bearing a neutron, have long been used as metabolic probes (Nelson and Trager, 2003), but few studies have assessed the potential of deuterated agents as pharmacotherapies (Harbeson and Tung, 2011;Braman et al, 2013;Gant, 2014). The molecular structures and pharmacologic activities of deuterated compounds (Harbeson and Tung, 2011), and even the structure and function of fully substituted enzymes (Di Costanzo et al, 2007), are extremely similar to their allhydrogen analogs.…”

“…The molecular structures and pharmacologic activities of deuterated compounds (Harbeson and Tung, 2011), and even the structure and function of fully substituted enzymes (Di Costanzo et al, 2007), are extremely similar to their allhydrogen analogs. Nonetheless, the metabolism of deuterated agents can differ substantially from nondeuterated compounds as a result of a phenomenon known as the deuterium isotope effect (Wiberg, 1955;Shao and Hewitt, 2010), which occurs as a result of the greater atomic mass of deuterium relative to hydrogen, causing deuterium-containing bonds with carbon, oxygen, and nitrogen to have lower vibrational frequencies than corresponding hydrogen-containing bonds.…”