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The page below is a sample from the LabCE course Drug Metabolism. Access the complete course and earn ASCLS P.A.C.E.-approved continuing education credits by subscribing online.

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Conjugation

Conjugates:
  • are highly polar.
  • are generally biologically inactive. The exception is morphine glucuronide, which is a more potent analgesic compared to the parent compound.
  • tend to be rapidly excreted in the urine.
  • with a high molecular weight compound attached are more likely excreted in the bile. The conjugate bond may be cleaved by intestinal flora with the parent compound released back to the systemic circulation. This process, known as "enterohepatic recirculation," results in delayed parent drug elimination and a prolongation of drug effects.
The products of phase II conjugation reactions have increased molecular weights and are usually inactive and less toxic. However, if you remember, phase I reactions can also produce active metabolites. In either case, the conjugated products are very water soluble and can be quickly eliminated by the kidneys.
Most of the transferases are located in the cytosol of cells, but UDP-glucurony transferase is located in the microsomes (a small particle in the cytoplasm of a cell), typically consisting of fragmented endoplasmic reticulum to which ribosomes are attached. Glucuronides are secreted in the bile and eliminated in the urine.
Glucuronidation is the most important phase II reaction. Glucuronic acid has several hydroxyl functional groups and a carboxylic acid functional group that makes it highly polar and very water soluble. Glucuronic acid conjugations are catalyzed by UDP- glucuronyl transferase. An example is the conjugation of glucuronic acid to morphine by UDP glucuronyl transferase to produce the metabolites morphine-6-glucuronide and morphine-3-glucuronide. Other examples of drugs that are conjugated by UDP-glucuronyl transferase are acetaminophen, codeine, naloxone (a medication used to block the effects of opiate overdose), temazepam (a benzodiazepine used to treat insomnia), the tricyclic antidepressants amitriptyline and imipramine, meprobamate, and the beta blocker propranolol. In addition, endogenous substances such as bilirubin, progesterone, testosterone, and thyroxine are conjugated by UDP-glucuronyl transferase.
Examples of substrates conjugated by sulfotransferases are minoxodil and dopamine.
Methylation and acetylation are contradictions to the notion that metabolism creates products that are more water soluble and unmasks functional groups that might be conjugated by other enzymes. On the contrary, they can decrease water solubility and mask functional groups that could have been conjugated. They can also create metabolites that are more toxic. An example is the acetyl metabolites of some of the sulfonamides. These metabolites are insoluble in urine and can precipitate out to form crystals in the urine.