Conjugation With Alpha Amino Acids

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Chapter: Biopharmaceutics and Pharmacokinetics : Biotransformation of Drugs

This reaction also occurs to a limited extent because of limited availability of amino acids.



PHASE II REACTION

CONJUGATION WITH ALPHA AMINO ACIDS

This reaction also occurs to a limited extent because of limited availability of amino acids.

The reaction occurs in two steps:

1. Activation of carboxylic acid drug substrate with ATP and coenzyme A (CoA) to form an acyl CoA intermediate. Thus, the reaction is a contrast of glucuronidation and sulphation where the donor coenzyme is activated and not the substrate.

2. Acylation of the -amino acid by the acyl CoA in presence of enzyme N-acyl transferase.

The reaction is summarized below.


where R’ = -CH2- (if glycine) or >CH-CH2-CH2-CONH2 (if glutamine)

Conjugation occurs commonly with glycine. Glutamine conjugation occurs to a lesser extent. Conjugation with other amino acids like aspartic acid, serine and taurine is still uncommon. The substrate is generally an acid (aromatic in particular) and the reaction product is an amide.

Examples of drugs forming glycine or glutamine conjugates are:

Aliphatic acids e.g. isopropoxyacetic acid

Alicyclic acids e.g. cholic acid

Aryl acids e.g. salicylic acid

Arylacetic acids e.g. phenylacetic acid

Heterocyclic aryl acids e.g. nicotinic acid.

Amino acid conjugation occurs extensively in the liver mitochondria and thus the reaction can be used to estimate hepatic function. The diagnostic marker used is benzoic acid which on conjugation with glycine yields hippuric acid. Hippuric acid is rapidly excreted in urine. Thus, the rate and extent of urinary excretion of hippuric acid following oral or i.v. administration of benzoic acid indicates functioning of liver. A decreased output indicates hepatic disorder.

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