Phase II Reactions

PHASE II REACTIONS

Phase II reactions involve transfer of a suitable endogenous moiety such as glucuronic acid, sulphate, glycine, etc. in presence of enzyme transferase to drugs or metabolites of phase I reactions having suitable functional groups to form highly polar, readily excretable and pharmacologically inert conjugates.

Phase II reactions are the real drug detoxication pathways because –

1. The conjugates/products of phase II reactions are absolutely free of pharmacological activity.

2. The conjugates/products of phase II reactions are highly polar and thus easily excretable either in bile or urine.

3. Tissue-reactive and carcinogenic metabolites formed as a result of phase I reaction are rendered harmless by conjugation with moieties such as glutathione.

The moieties transferred to the substrates (called as conjugating reagents) in a phase II reaction possess 3 characteristics:

1. They are simple endogenous molecules such as carbohydrates, proteins and fats.

2. They are of large molecular size.

3. They are strongly polar or ionic in nature in order to render the substrate water-soluble.

Two outstanding characteristics of conjugation reactions are –

1. The reaction involves an initial activation step – either

(a) The drug is activated e.g. conjugation with amino acids and acetylation reaction; or

(b) The conjugating reagent is activated e.g. glucuronidation, sulphation and methylation.

2. The reaction is capacity-limited – the limited capacity of conjugation reactions is attributed to –

(a) Limited amount of conjugating agent, for example, glycine.

(b) Limited ability to synthesise the active nucleotide intermediate.

(c) Limited amount of enzyme conjugate transferase.

Thus, when doses of drugs are higher than normal levels of conjugating molecules, saturation of metabolism occurs and the unconjugated drug/metabolite precipitates toxicity. The order of capacities of important conjugation reactions is –

Glucuronidation > Amino Acid Conjugation > Sulphation and Glutathione Conjugation

The increase in the molecular weight of the drug following conjugation with glucuronic acid, sulphate and glutathione is 176, 80 and 300 Daltons respectively.

The molecular weight of the conjugate is important in dictating its route of excretion –

^·            High molecular weight conjugates (>350) are excreted predominantly in bile

^·            Low molecular weight conjugates (<250) are excreted in urine.

Thus, glutathione conjugates are always excreted in bile.

Table 5.3 compares the various phase II reactions.

TABLE 5.3

Phase II Reactions and their Characteristics