02.03.3 Phase II: Conjugation

The second phase of drug metabolism is conjugation, which is a Phase I metabolite joining to another compound. Conjugation is very important, as this is the phase that increases the water solubility of the drug, which is needed to allow excretion of the drug. The conjugation substates are naturally occurring substances with the most common Phase II conjugation products being glucuronides and sulphates. Glucuronic acid is a product of glucose metabolism, and conjugation with glucuronic acid forms glucuronide metabolites. In addition to increasing water solubility, conjugation with glucuronic acid has another important function, it inactivates the drug. This is because the glucuronide metabolites are inactivate.

Some glucuronide metabolites are excreted by the kidney in the urine. However, many glucuronide metabolites are transported in the bile to the gastrointestinal tract and undergo enterohepatic recycling (Figure 2.5). In addition, some glucuronide metabolites are partly excreted from the kidney, and partly transported in the bile acid.

Figure 2.5 Entero-hepatic recycling (Copyright QUT, Sheila Doggrell)

In enterohepatic recycling, Drug C arrives at the liver in the circulation. The metabolism of Drug C involves conjugation with glucuronic acid to form Drug C glucuronide that is transported in the bile to the gastrointestinal tract. Once in the gastrointestinal tract, some of the glucuronide is excreted in the faeces, and some of it may be deconjugated by the bacterial enzyme β-glucuronidase to yield back the active Drug C, that can be reabsorbed, and taken to the liver, with some of the active drug re-entering the circulation.

Many glucuronides undergo this recycling, and this alters their kinetics (the relationship between plasma concentration and time). The plasma levels may be higher than expected because the drug is being recycled. To counter this, the dose of a drug may need lowering. An example of a drug that undergoes this recycling is glicazide, which is used in the treatment of type 2 diabetes. As type 2 diabetes is very common among indigenous Australians, it was of interest to determine whether there were any genetic differences in the recycling of glicazide by Caucasians and indigenous Australians. It was found that there is a slight difference, 30% of the dose in Caucasians is recycled compared to 20% in the indigenous group. Theoretically, this means that for the same dose, the plasma levels could be lower in the indigenous group meaning the the glycaemic control might be slightly lower.

When antibiotics are administered they kill the good as well as the bad (disease causing) bacteria. By killing the good bacteria in gut, antibiotics inhibit bacterial enzyme β-glucuronidase, which inhibits the enterohepatic recycling. Without this recycling of a glucuronide, plasma drug levels may be lowered, and the drug may become ineffective. For instance, oral contraceptives undergo enterohepatic recycling, and with antibiotic use, the plasma levels are reduced which may lead to the preparations providing less contraceptive benefit. This could result in unplanned/unwanted pregnancy..