Page 192 - Medicinal Chemistry Self Assessment

2.17 Hydrocortisone 181

some limited solubility in water. By forming a lipophilic ester with the primary alcohol at C-21,
the overall water solubility of the drug decreases substantially. In this case, one of the hydrophilic
groups is now masked as an ester, thereby significantly decreasing its hydrophilic character. As a
lipophilic prodrug, hydrocortisone can be formulated as a suspension for intramuscular or subcu-
taneous injection.

5. Lipophilic glucocorticoid esters typically do not concentrate in the urine, but rather undergo glomer-
ular filtration followed by tubular reabsorption. Provide a brief rationale for why lipophilic glucocor-
ticoid esters do not concentrate in the urine and determine what effect this has on duration of drug
action.
Answer
For drugs to concentrate in the urine, they need to be highly water soluble (contain functional
groups with a significant amount of hydrophilic character). We have already evaluated the overall
water solubility of hydrocortisone to be relatively poor, despite the presence of several hydrophilic
functional groups. The addition of a lipophilic ester will further decrease the water solubility of
the resulting glucocorticoid ester. Because the glucocorticoid ester suffers from poor water solu-
bility, it is not unexpected that it does not concentrate in the urine. These lipophilic esters, however,
have sufficient hydrophobic character to undergo reabsorption in the renal tubules. Because the
drug is returned to systemic circulation via this route of absorption, the duration of drug action is
prolonged.

6. Which type of prodrug, water soluble ester salts, or lipophilic esters, would you anticipate to have
greater systemic side effects?
Answer
The more water soluble the prodrug is, the wider the systemic distribution. The greater the prodrug’s
solubility in the blood, then the greater the potential is for more misadventures/side effects. Because
the water soluble ester salts are by far more water soluble than the lipophilic esters, one would
predict that the water soluble ester salts would exhibit more systemic side effects.