BIOTRANSFORMATION
Biochemical alteration of chemicals such as (but not limited to) nutrients, amino acids, toxins, and drugs in the body
It is also needed to render nonpolar compounds polar so that they are not reabsorbed in renal tubules and are excreted.
The body typically deals with a foreign compound (DRUGS) by making it more water-soluble, to increase the rate of its excretion through the urine
Site and enzymes used in biotransformation
Site : usually liver Enzymes:
Enzymes
MICROSOMAL ENZYMES A group of enzymes
associated with a certain particulate fraction of liver homogenate.
These are a mixed function oxidase system or monooxygenases.
These requires NADPH and oxygen.
NON MICROSOMAL ENZYMES
These are present in the cytoplasm and mitochondria of hepatic cells as well as in other tissues including plasma.
The 2 most imp. Microsomal enzymes:1. NADPH cyt.
P450 reductase
2. Cut. P450
Phases of biotransformation
Phase I
• Includes oxidative, reductive, and hydrolytic reactions.
• In these type of reactions, a polar group is either introduced or unmasked, so the drug molecule becomes more water-soluble and can be excreted.
• Reactions are non-synthetic in nature and in general produce a more water-soluble and less active metabolites
Phase II •These reactions involve covalent attachment of small polar endogenous molecule such as glucuronic acid, sulfate, or glycine to form water-soluble compounds.•This is also known as a conjugation reaction.•The final compounds have a larger molecular weight.
Phase I reactions
Oxidation Reduction Hydrolysis
Oxidation reactions
Process of addition of oxygen or removal of hydrogen from a drug molecule.
hydroxylation •Phenytoin hydroxyphenytoin
dealkylation •Codeine morphine
S-oxidation •Cimetidine cimetidine sulfoxide
deamination •Amphetamine benzylmethylketone
Reduction reactions
Addition of hydrogen or removal of oxygen from a drug molecule.
Nitro reduction : chloramphenicol arylamine Keto reduction: cortisone hydrocortisone
Hydrolysis
Process where a drug molecule is split by the addition of a molecule of water.
Both microsomal and non-microsomal enzymes maybe involved.
Eg: acetylcholine+ H2O choline + acetic acid
Phase 2 reactions
Glucuronide conjugation
Most common type of metabolic reaction
Drug + UDPGA drug glucuronide + UDP
Glucuronyl transferase
excreted
Glutathione conjugation
Glutathione –s –transferase
Sulfate conjugation
Enzyme : sulfotransferases
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