Page 183 - Medicinal Chemistry Self Assessment

172 Medicinal Chemistry Self Assessment

Answer

Name of Metabolic Transformation
A Oxidative deamination
B Aromatic hydroxylation
C Oxidative O-dealkylation
D Oxidative O-dealkylation followed by alcohol oxidation
E Allylic oxidation*
F Acetylation
*Note: This carbon–nitrogen double bond acts similarly to a carbon–carbon double bond. If a carbon
substituent attached to this carbon–nitrogen double bond bears a hydrogen atom, then it can
undergo oxidation. In this case, there is only one carbon substituent that fulfills that criterion, and
there is only one location possible for an allylic oxidation to occur.

6. Fluvoxamine is a strong inhibitor of CYP1A2, CYP3A4, and CYP2C19. These enzyme isoforms catalyze
a number of the phase I oxidative metabolic transformations. Several of the benzodiazepines (used
in the treatment of anxiety), including the very popular alprazolam, rely heavily on hepatic oxidation
for metabolic inactivation and elimination. Other benzodiazepines, including the equally popular
lorazepam, rely on glucuronide conjugation for metabolic inactivation and elimination. Which
combination of drugs, fluvoxamine + alprazolam or fluvoxamine + lorazepam, is the most likely to
generate an enhanced anxiolytic effect?
Answer
Fluvoxamine inhibits several of the metabolism isoforms that catalyze oxidative metabolic transforma-
tions. Alprazolam relies on hepatic oxidation for metabolic inactivation and elimination. If fluvox-
amine inhibits the same enzymes that alprazolam relies on for hepatic oxidation, then the levels of
active alprazolam will exist for a longer period of time than expected. With more alprazolam avail-
able to produce an anxiolytic effect for a longer period of time, it is likely that an enhanced anxio-
lytic effect will be observed.
Because lorazepam relies on a different set of enzymatic isoforms for glucuronide conjugation, the
co-administration of fluvoxamine will have little or no effect on the metabolic inactivation and elimi-
nation of lorazepam, and an enhanced anxiolytic effect will not be observed.