Drugs are metabolized in two major ways: modification of their chemical structure (termed Phase 1), and linking to an endogenous substance (termed Phase 2). Both ways involve chemical reactions and both tend to decrease efficacy (e.g., by decreasing the goodness of “fit” to a receptor) and to increase elimination rate (e.g., by making the molecule more hydrophilic). All of these reactions involve the breaking of bonds and the making of new bonds. Most of these reactions are catalyzed by enzymes. The effectiveness of catalysis is determined by the specific atoms and the 3-dimensional shape of the drug molecule, and the complementary fit with the enzyme. An alteration in any one of these components will alter the efficiency of catalysis, and hence the rate of drug metabolism (Figure 2). Common chemical reactions involved in the metabolism of drugs include one or more “non-synthetic” types (e.g., involving oxidation, reduction, hydrolysis, cyclization, decyclization, or the addition of oxygen or removal of hydrogen) and “synthetic” types, which involve joining (conjugation) the drug molecule with an endogenous substance (such as glucuronic acid to form

glucuronides). Many of these reactions involve the making or breaking of hydrogen bonds either directly or in the transition state (e.g., conversion of C-H to C-OH) [5] .

As a drug molecule is metabolized to one or more metabolite molecules, it proceeds to a lower-energy state. But it must pass through the transition state, which is at higher energy than is the parent drug molecule (Figure 3) [5] . Enzymes facilitate the reaction by lowering the activation energy needed to get to the transition state. Carbon bonds are almost always involved, e.g., C-H, O-H, N-H, etc.

Deuterium is a stable isotope of hydrogen. In contrast to the more common hydrogen isotope on Earth (one proton and no neutron in the nucleus), the nucleus of deuterium consists of one proton and one neutron (Figure 4). It is not radioactive, as is tritium (one proton and two neutrons).

The effect of deuterium is summarized by Blake et al. (1975): [6]

The difference in mass between deuterium and hydrogen causes the vibrational frequencies of carbon, oxygen, and nitrogen bonds to deuterium to have lower frequencies than corresponding bonds to hydrogen. As a result, the chemical bonds involving [deuterium] will general be more stable than those of [hydrogen].

…The more stable deuterium bond requires a greater energy of activation to achieve the transition state; as a consequence, the rate of reaction involving a bond to deuterium is generally slower than that involving a bond to hydrogen. Thus, substitution of deuterium for hydrogen in a chemical bond can affect significantly the rate of bond cleavage and exert marked effects on the relative rates of chemical reactions.

Large isotope effects on reaction rates are apparent where cleavage involves a bond to deuterium at the reaction site.

An observable isotope effect will only be apparent, of course, where the breaking of a C-H or C-D bond is involved in the rate-determining step.

Efforts to modify the pharmacology of drugs by using deuterium date back at least several decades. As reviewed by Blake et al. (1975) [6] , the effect of deuterium on the duration (metabolism) of a variety of classes of drugs have been investigated, including barbiturates, anesthetics, antibiotics, and others.

The first U.S. FDA-approved deuterated drug is deutetrabenazine (AUSTEDO®; by Teva Pharmaceutical Industries) to treat the involuntary movements (chorea) of Huntington’s disease. Tetrabenazine has been used clinically for many years as treatment for movement disorders. The molecule has two methoxy groups, which are targets of rapid metabolism to demethylated metabolites that subsequently undergo Phase 2 conjugation reactions. Deutatetrabenazine (Figure 5) [7] is metabolized at a slower rate than is non-deuterated tetrabenazine, which imparts less patient-to-patient variability and a dosing advantage to the deuterated drug.