General and Systematic Veterinary Pharmacology

Phase-II reactions - Synthetic reactions

PHASE - II REACTIONS

• Conjugation of a functional group to the drug or its metabolite to make it water soluble
• The presence of –OH, -COOH, -NH₂, -SH groups favour formation of conjugates (these groups are added to (or) exposed in Phase I)

Glucuronidation

• The most important reaction – most drugs incl. endogenous steroids and bile pigments undergo this reaction.
• Glucuronide conjugation takes place in microsomes.
• The source of glucuronide is UDPGA through glucuronyl transferase.
• The product is highly soluble and is excreted by urine (if MW<300 – 500) or via bile ( if >500)
• Beta -glucuronidase in intestine may liberate the active drug which is again reabsorbed and undergoes enterohepatic recirculation which leads to longer duration of action of the drug

Sulfate conjugation (non-microsomal)

• Forms ethereal sulfates - eg. Phenols, acetaminophen, morphine and endogenous heparin, chondroitin and some steroids

Acetylation (non microsomal)

• Acetylates are formed eg. Sulphonamides --- acetyl CoA is the donor
• Acetylates are poorly soluble in water and lipid and are likely to cause crystalluria

Methylation (non-microsomal)

• Adds methyl radicals – The aminoacids methionine and cysteine are the donors
• eg. Histamine, adrenaline, sex steroids

Glycine conjugation (non-microsomal)

• Not a major pathway, eg. Salicylates

Glutathione conjugation

• Not a major pathway – forms mercapturic acids – important for removal of toxic radicals (superoxides, epoxides and toxic intermediates)

Ribonucleoside / Ribonucleotide synthesis

• These reactions are important for the activation of purine and pyrimidine antimetbolites used in cancer therapy
• Drug conjugates were once believed to represent terminal inactivation events and as such have been viewed as “true detoxification” reactions.
• However, this concept must be modified, since it is now known that certain conjugation reactions may lead to the formation of reactive species responsible for the hepatotoxicity of the drug.