Page 179 - Medicinal Chemistry Self Assessment

3. The calculated for difference in this pharmacokinetic property.

Fenofibrate

4. From an elimination NOT occur).

O
O
O
O
H
OH
CH
C
H
3
3
Cl
B
A

C Gemfibrozil

168 Medicinal Chemistry Self Assessment

5. Provide a structural rationale for why oxidative O-dealkylation does not occur.
5. Provide a structural rationale for why oxidative O-dealkylation does not occur.
Answer:
Answer
1 2

Oxidative O-dealkylation transformations occur with ethers that have at least one α-carbon (adja-
cent carbon atom) with at least one hydrogen atom attached. Evaluation of the ether found within

the structure of fenofibrate reveals that one of the carbons (#1) attached to the ether oxygen atom
is part of an aromatic ring. It does not have a hydrogen atom attached to it. Carbon #2, attached
to two aliphatic alkanes (methyl groups) and a carboxylic acid, also does not have a hydrogen atom
attached to it. Because neither of the α-carbons has at least one hydrogen atom attached to it, this
ether is not subject to oxidative O-dealkylation.

6. Fenofibrate and gemfibrozil have dramatically different elimination half-lives (20–22 hours and 1.5
1.14 and 2.14 (drug name – remove bold)
hours respectively). Identify the possible metabolic transformations for gemfibrozil and provide a
justification for the significant difference in this pharmacokinetic parameter.

Fenofibrate Gemfibrozil

Answer
Letter “C” – add bold
Possible phase I metabolic transformations:
• Benzylic oxidation (two different locations)*
• Oxidative O-dealkylation
• Aromatic hydroxylation (multiple)

*Note: Each benzylic hydroxyl group can be further oxidized to carboxylic acids.

Possible phase II conjugation transformations:
C
• Glucuronide conjugation
• Amino acid conjugation (with glutamine, glycine, arginine or taurine)
2.14 – remove bold from label

The difference in aromatic substituents between the two drugs has a large impact on the number of
B potential phase I transformations that produce more water soluble metabolites. Oxidative O-
F
dealkylation not only generates more water soluble products, but also splits gemfibrozil in half,
D
A causing drug deactivation. Based on this assessment, it is no surprise that there is a difference in the
C
elimination half-lives of these two drugs and that gemfibrozil is eliminated much more rapidly.

E

Fenofibrate

2.14 – remove bold from label

O O CH 3 O O
Ester
O Hydrolysis O
O CH 3 OH
H 3 C CH 3 H 3 C CH 3
Cl Cl

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