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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