Drug Metabolism

Drug metabolism refers to the set of reactions by which drugs are converted into other compounds that are either used by the body or excreted. Our bodies dispose of the medications we ingest by a variety of metabolic pathways. One common metabolic pathway is called glucuronic acid conjugation, or simply glucuronidation. This process is very similar to all of the SN2 processes that we investigated in the previous section. Specifically, a bad leaving group (hydroxyl) is first converted into a good leaving group, followed by nucleophilic attack. Glucuronidation exhibits the same two key steps.

1. Formation of UDPGA (uridine-5’-diphospho-a-d-glucuronic acid) from glucose involves conversion of a bad leaving group into a good leaving group.

UDPGA is a compound with a very good leaving group. This large leaving group is called UDP. In this transformation, one of the hydroxyl groups in glucose has been converted into a good leaving group.
2. Next, an SN2 process occurs in which the drug being metabolized (such as an alcohol) attacks UDPGA, expelling the good leaving group.

This SN2 process requires an enzyme (a biological catalyst) called UDP-glucuronyl transferase. The reaction proceeds via inversion of configuration (as expected of an SN2 process) to produce a b-glucuronide, which is highly water soluble and is readily excreted in the urine.
Many functional groups undergo glucuronidation, but alcohols and phenols are the most common classes of compounds that undergo this metabolic pathway. For example, morphine, acetaminophen, and chloramphenicol are all metabolized via glucuronidation:

In each of these three compounds, the highlighted hydroxyl group attacks UDPGA. Glucuronidation is the main metabolic pathway by which these drugs are eliminated from the body.