Page 150 - Medicinal Chemistry Self Assessment

2.9 Aripiprazole 139
4. Using your answers from the previous

4. Drug molecules that are highly plasma protein bound may undergo a drug interaction due to the
5. Drug molecules or losartan?
displacement of one drug molecule from a plasma protein by another drug molecule. Shown below
are the structures of tolbutamide and losartan. Both of these drugs are highly plasma protein bound.

Aripiprazole is also highly plasma protein bound (>99%). Would you expect there to be a drug inter-

action between aripiprazole and either tolbutamide or losartan?

4. Using your answers from the previous

Tolbutamide
5. Drug molecules or losartan?
Losartan

Answer
The answer here is no. Tolbutamide and losartan are acidic drug molecules due to the presence of
6. Assume that this that this binding interaction occurs at a physiological pH of 7.4.
an acidic sulfonylurea and a tetrazole functional group, respectively. Aripiprazole is a basic drug

molecule due to the presence of a tertiary amine and an aromatic amine. Acidic drug molecules
primarily bind to albumin, whereas basic drug molecules primarily bind to α1-glycoprotein. Plasma
D
protein binding interactions (also known as plasma protein displacement interactions) occur due to
the nonspecific nature of the plasma proteins that bind and transport drug molecules. These types of
A
interactions are only therapeutically important when the drug molecules are highly plasma protein
C
bound (i.e., over 90%). Although this is true of all three drugs, the difference in their acid/base
nature significantly decreases the probability of a drug interaction due to plasma protein displace-
B
ment. Tolbutamide

Aripiprazole Losartan

5. Assume that the boxed functional groups of aripiprazole form four key binding interactions with

a serotonin receptor. Further assume that these binding interactions occur with the side chains of
Tyr, Asp, Ile, and Gln. Using this information, identify four possible binding interactions between

aripiprazole and the given amino acids. Assume that this binding interaction occurs at a physiological
6. Assume that this that this binding interaction occurs at a physiological pH of 7.4.
pH=7.4.

D
A
C
B

Aripiprazole