Page 162 - Medicinal Chemistry Self Assessment

2.11 Cetirizine 151

3. Based on your structural evaluation of both hydroxyzine and cetirizine, name ALL of the phase I
metabolic transformations possible.
Answer
• Oxidative O-dealkylation
• Oxidative N-dealkylation
• Alcohol oxidation
• Aromatic hydroxylation (less likely on halogenated aromatic hydrocarbon)
NOTE: Although there is a benzylic carbon with a hydrogen atom attached to it, benzylic oxidation
does not occur because the benzylic carbon is already directly attached to another heteroatom (N).

4. A metabolic product from a phase II metabolic transformation has been identified. Which phase II
transformations can cetirizine undergo?

Answer
The carboxylic acid can undergo phase II transformations including glucuronidation and amino acid
conjugation (with glutamic acid and glycine [major], and aspartic acid, serine, and taurine [minor]).
(NOTE: the glucuronide conjugate is the metabolite that has been identified.)

5. Review the structure of cetirizine (pK =2.9 and 8.3) and identify all of the acidic and basic functional
a
groups present. Determine the predominant ionization state of each functional group as it travels
through several compartments of the body after oral administration. Complete the table below.
Answer

Ionized or Ionized or Ionized or
Name of Acidic or Ionized or Unionized Unionized Unionized at Ionized or
Functional Basic Unionized at at pH=1 at pH=7.4 pH=8 Unionized at
Group (pK ) pH=5 (saliva) (stomach) (plasma) (intestine) pH=6 (urine)
a
Tertiary amine Basic Ionized Ionized Ionized Ionized Ionized
(piperazine) pK 8.3
a
Carboxylic acid Acidic Ionized Unionized Ionized Ionized Ionized
pK 2.9
a

6. Provide a structural rationale for why hydroxyzine is classified as a sedating antihistamine and cetiri-
zine is categorized as a non-sedating antihistamine.
Answer
Hydroxyzine contains functional groups that contribute to the overall hydrophobic character of the
molecule (e.g., aromatic hydrocarbon, halogenated aromatic hydrocarbon, aliphatic alkane), as well
as functional groups that contribute to the hydrophilic character of the molecule (e.g., ether, primary
alcohol, and tertiary amines/piperazine). The hydrophilic character of the molecule enhances its
water solubility, whereas the hydrophobic character enhances its ability to be absorbed across lipid
bilayer membranes. At pH=7.4, the tertiary amine will be predominantly in its ionized form which
will further increase the water solubility of the molecule.
The hydrophilic character contributes to the ability of the drug to be distributed in the body in the
aqueous plasma. The hydrophobic character contributes to the ability of the drug to be absorbed
across the membranes of the gastrointestinal tract and eventually across the blood–brain barrier. It
is important to remember that the tertiary amine (one of the two) will be predominantly ionized at
physiological pH. Because an equilibrium exists between the ionized and unionized form of the drug,
some fraction of the drug will be unionized at any point in time and, therefore, can cross the blood–
brain barrier and have an effect on the histamine receptors.