By observing the relative activity of a drug and its derivatives under various conditions and delivery systems, it is possible to piece together a explanation of how the drug is chemically altered, or not altered, depending on where it travels throughout the body.
Consider a drug with an ionized carboxyl group that shows good activity against its targets in vitro. In vivo, the drug showed poor activity when ingested orally, but not when injected intravenously. Additionally, when this drug was converted to an ester, it had poor activity in vitro, but strong activity when administered orally.
The behavior of the drug and its ester derivative can be explained as a consequence of the first pass effect, wherein an orally ingested drug gets subjected to metabolic modifications in the liver that may compromise its activity. The above observations indicate that this is exactly what happens with the original drug molecule, as its active ionized carboxyl group does not survive the metabolism in the liver.
However, when the drug is chemically modified into an ester, a curious thing happens. Although the esterified drug lacks the activity of its active counterpart in the in vitro studies, the first pass effect ends up converting the esterified drug into its active form.
As a result, in contrast to the unaltered active drug molecule, while the ester derivative of the drug would prove ineffective when taken intravenously, it would actually work effectively if taken orally.