Metabolism

Metabolism

Metabolism is also known as bio transformation, which means chemical alteration of the drug in the body. In general, metabolism reactions generate more polar (water soluble) and inactive metabolites that are readily excreted from the body.  

The lipophilic (lipid soluble) characteristics of the drugs that promote their passage through biological membranes and subsequent access to their sites of action hinder their excretion from the body. 

Metabolism Cycle

In simple language –

Lipid solubility is necessary for absorption or penetration by cell membrane and water solubility is necessary for the excretion of drug through the kidney tubules and other suitable routes.

The process, which involves in the lipid soluble molecules change into water soluble molecule called metabolism.

OR

The process, which involves in the non-polar compound change into polar compound called metabolism.

Site of metabolism

1. Primary site of metabolism is liver.
2. Secondary sites of metabolism are kidney, intestine, lung, plasma & skin.

Metabolism or biotransformation of drugs may lead to the following

Inactivation (Drug after metabolism less active or inactive).

Active metabolite from an active drug. 

Activation of inactive drug (inactive drug after metabolism produce active metabolites these type drug know as prodrug). 

Metabolism is enzymatic reaction in which various microsomal or non-microsomal enzymes are involved. 

Microsomal Enzyme

Microsomal enzymes are present on smooth endoplasmic reticulum, primarily in liver, also in kidney, intestinal mucosa and lungs. They need NADPH and oxygen.  

For example –Monooxygenase, Cytochrome P-450, epoxide hydrolases, UDP-glucuronosyl transferase (UGTs) etc.  

Non-microsomal Enzyme

These are present in the mitochondria and cytoplasm of hepatic (liver) cells.    

Classification of metabolism reaction

Drug metabolism or biotransformation reactions are classified into two phase   

1. Phase I reaction or Non-synthetic reaction or functionalization reaction.
2. Phase II reaction or synthetic reaction or conjugation reaction.

Metabolism Reaction

Phase I reaction or Non-synthetic reaction or functionalization reaction.

Phase I reactions expose or introduce a functional group on the parent compound such as occurs in hydrolysis reactions. 

Phase I reactions generally result in the loss of pharmacological activity. 

Phase I reactions function to convert lipophilic molecules into more polar molecules by unmasking or introducing a polar functional group, such as –NH2 or –OH. A functional group is generated or exposed metabolite may be active or inactive. Phase I metabolism may increase, decrease or leave unaltered the drug’s pharmacologic activity.
 

Phase 1

In phase I involve many reactions –

Oxidation

In oxidation reaction, addition of oxygen molecule or negative charged radical to drugs. OR, removal of hydrogen molecules or positive charged radical to drug.
 

Oxidative reactions are mostly carried out by a group of mono-oxygenases in the liver. 

Two type of oxidation occur in metabolism

Microsomal oxidation reaction

Many reactions are involved such as hydroxylation, dealkylation and s-oxidation.

Hydroxylation – In this reaction, addition of hydroxyl group. 

For example – Phenytoin after metabolism change into hydroxyphenytoin. Salicylic acid after metabolism change into getisic acid.

Dealkylation – In this reaction, removal of alkyl group.  

For example – Codeine after metabolism change into morphine. 
    

S-oxidation – In this reaction, addition of sulfoxide group.  

Example – cimetidine after metabolism change into cimetidine sulfoxide.

  

Nonmicrosomal oxidation reaction

Oxidation can also be catalyzed by nonmicrosomal enzyme.

Example of non-microsomal enzymes – Monoamino oxidase (MAO), Xainthine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase. 

Reduction Reaction – In this reaction addition of hydrogen or positive charged radical to drug / removal of oxygen or negative charged radical to drug. 

Type of reduction reaction

Nitro reduction reaction – Addition of nitro group in the drug molecule.

Keto reduction reaction – Addition of keto group in the drug molecule.

Hydrolysis reaction - In this reaction of splitting of drug molecules in the presence of water molecule. 

For example –  Acetylcholine + water = choline + acetic acid

Cyclization reaction – In this reaction, formation of ring structure from a straight chain compound. 

Example – Proguanil.

Decyclization reaction – opening up of ring structure of the cyclic drug molecules.  

Example – Phenytoin , barbiturates etc.   

Note –   if Phase I metabolites are not sufficient polar to elimination than these metabolites goes in Phase II reaction and become more polar metabolites for excrete out.  

Phase II reaction / synthetic reaction / conjugation reaction

If the metabolites from phase I metabolism is sufficient polar than it can be excreted by the kidneys or renal. Many metabolites are too lipophilic to be retained in the renal tubules. Some drugs are directly involved in Phase II reaction. Drugs and phase I metabolites are form highly ionized organic acid which is easily excreted in urine or bile. A subsequent conjugation reaction with an endogenous substrate including glucuronic acid, acetic acid, amino acid or sulfuric acid result in more water soluble metabolites that are most often therapeutically inactive. 

Conjugation reactions have required high energy and rate of reaction also fast.

High molecular weight drugs are excreted by bile. 

Low molecular weight drugs are excreted by urine. 

    
Various types of reactions are involved in phase II reaction.

Phase 2

Glucuronide conjugation

Glucuronide conjugation reaction carried out by UDP glucuronosyl transferase (UGTs) enzyme.  

Glucuronic acid conjugated with the hydroxyl or carboxylic group containing compounds. 

Glucuronic acid is containing high molecular weight. After conjugation of glucuronic acid compound molecular weight is increases which favors its excretion in bile.  

Example – Paracetamol, Aspirin, diazepam, chloramphenicol, metronidazole, morphine etc.
Some endogenous substrates including bilirubin, thyroxine and steroidal hormones are also metabolized by this pathway. 

Methylation

The phenols & amines can be methylated by methyl transferases (MT), cysteine and methionine acting as methyl donors. 

Example – histamine, nicotinic acid, adrenaline, methyldopa mercaptopurine, Captopril etc.
 

Acetylation

Drugs or compounding having hydrazine or amino residues are conjugated with the help of acetyl coenzyme – A. 

Example – isoniazid, dapsone, procaiamide etc.   

Glycine Conjugation

Nicotinic acid, salicylates and other drugs having carboxylic acid group are conjugated with glycine.  

Sulfate conjugation  

The phenolic compounds and steroids are sulfated by sulfotransferases (SULTs). 

Examples – adrenal steroids, methyldopa, choramphenicol & sex steroids.