Drug metabolism, also known as biotransformation, is the process by which the body modifies drugs and other xenobiotics.
This process often renders the substances more soluble, allowing them to be excreted from the body.
Metabolism also can deactivate drugs, activate prodrugs, or even result in the formation of metabolites that are pharmacologically active or toxic.
The liver is the primary site of drug metabolism, although other tissues such as the gut, kidneys, and lungs also play roles.
Phases of Drug Metabolism
Drug metabolism is a process that transforms lipophilic drugs into more polar compounds to facilitate their elimination from the body.
This process usually occurs in two phases: Phase I and Phase II.
Phase I Metabolism
Phase I metabolism involves reactions that introduce or unmask a functional group (-OH, -NH2, -SH) on the drug molecule, thereby increasing its polarity.
These reactions generally involve oxidation, reduction, or hydrolysis.
1.Oxidation:
This is the most common type of Phase I reaction.
The enzymes involved are primarily from the cytochrome P450 (CYP450) family, a group of heme-containing enzymes found mainly in the liver but also in the intestines and other tissues.
Oxidation reactions often involve adding an oxygen atom to the drug molecule or removing a hydrogen atom.
Examples include hydroxylation, dealkylation, and sulfoxidation.
2.Reduction:
This reaction involves the gain of electrons or the loss of oxygen and usually occurs with nitro compounds, azo compounds, and certain carbonyl groups.
3.Hydrolysis:
This is the breaking of a compound into two parts by the addition of a water molecule.
Esterases and amidases are the enzymes that typically perform these reactions, cleaving ester and amide bonds, respectively.
Phase I reactions can result in the formation of metabolites that are more active, less active, or have similar activity to the parent drug. Some Phase I metabolites may also be toxic.
Phase II Metabolism
Phase II metabolism involves conjugation reactions that attach a polar moiety to the drug or a Phase I metabolite, further increasing its water solubility.
These reactions generally do not occur without Phase I reactions taking place first, but there are exceptions.
1.Glucuronidation:
This is the most common Phase II reaction.
The enzyme uridine diphosphate glucuronosyltransferase (UGT) catalyzes the transfer of glucuronic acid to the drug or Phase I metabolite.
The glucuronide conjugate is highly polar and easily excreted in the urine or bile.
2.Sulfation:
Sulfotransferases (SULT) catalyze the transfer of a sulfate group to the drug.
Sulfation usually occurs with phenols, alcohols, and amines.
3.Acetylation:
Acetyltransferases catalyze the transfer of an acetyl group from acetyl coenzyme A to the drug.
This reaction usually occurs with amines.
4.Methylation:
This reaction involves the addition of a methyl group to the drug, usually at oxygen, nitrogen, or sulfur atoms.
5.Glutathione Conjugation:
This reaction generally occurs with electrophilic compounds and results in the formation of conjugates that are eventually excreted in the urine or bile.
Phase II reactions typically result in the formation of metabolites that are less pharmacologically active than the parent drug.
However, in some cases, Phase II reactions can lead to the formation of active or even toxic metabolites.