General and Systematic Veterinary Pharmacology

Phase-I Biotransformation - oxidation reactions and others

PHASE-I BIOTRANSFORMATION

• Although every tissue has some ability to metabolize drugs, the liver is the principal organ of drug metabolism. Other tissues that display considerable activity include the gastrointestinal tract, the lungs, the skin and the kidneys.
• Drug biotransformation in vivo can occur by spontaneous, noncatalysed chemical reactions (Hofmann degradation), which however is very rare.
• The vast majority of xenobiotics undergo biotransformation the reactions of which are catalysed by specific cellular enzymes. At the subcellular levels, these enzymes may be located in the endoplasmic reticulum, mitochondria, cytosol, lysosomes or even the nuclear envelope or plasma membrane.
• Many drug metabolising enzymes are located in the lipophilic membranes of the endoplasmic reticulum of the liver and other tissues. When these lamellar membranes are isolated, they re-form into vesicles called microsomes. The rough microsomes tend to be dedicated to protein synthesis and the smooth microsomes are relatively rich in enzymes responsible for oxidative drug metabolism. They contain the important class of enzymes known as the Mixed Function Oxidases or monooxygenases or CYP 450 enzymes (Cytochrome P450 enzyme system)

Microsomal enzymes / mixed function oxidases

• catalyse oxidative and glucuronide conjugation reactions
• Requires molecular O₂, CYP 450 ( a heme protein), NADPH (reduced nicotinamide adenine dinucleotide phosphate )
• NADPH + CYP 450 (A)+H⁺ AH₂ + NADP⁺
• AH₂ + O₂ ‘active oxygen complex’
• Drug + ‘active oxygen complex’ oxidized drug + A + H₂O