Biotransformation (Metabolism) of Drug

Biotransformation means chemical alteration of the drug in the body. By this process, a drug may either be inactivated or converted into a more active compound. It is needed to provide non-polar (lipid soluble) compounds to polar (lipid insoluble) compounds so that they are not reabsorbed in the renal tubules and are excreted. Most hydrophilic drugs like streptomycin, neostigmine etc. are not biotransformed and are excreted unchanged. Biotransformation reduces the duration of action of drug and decrease the toxicity of the drug.

Site of Biotransformation:

Biotransformation of the drugs occurs mainly in the liver. Other minor sites of biotransformation are kidney, plasma, placenta, gastrointestinal tract, skin and lungs. In the liver the drug metabolizing enzymes are present in microsomes. So, these enzymes are called as ‘hepatic microsomal drug metabolizing enzymes’. The enzymes system involves in phase I reactions are located primarily in the endoplasmic reticulum, while the phase II conjugation system enzymes are mainly cytosolic.

Biotransformation of drugs may lead to the following.

I) Inactivation – Pentobarbitone , morphine, chloramphenical.

II) Active Metabolite from an Active Drug-

Phenacetin                                                                        Paracetamol

Digitoxin                                                                            Digoxin

Codeine                                                                             Morphine

Primidone                                                                          Phenobarbitone

Imipramine                                                                         Desipramine

III) Activation of Inactive Drug-

Few drugs are inactive as such and conversion in the body to one or more active metabolites. Such a drug is called a pro-drug.

Pro-Drug                                                                                  Active Form

Levodopadopa                                                                           Dopamine

Prednisone                                                                                 Prednisolone

Bacampicillin                                                                              Ampicillin

Methods of Biotransformation:

The reactions which bring about biotransformation of drugs can be classified as:

  •  Non-synthetic reactions (phase I reactions)
  •  Synthetic reactions (phase II reactions)

1. Non-synthetic reactions

Non-synthetic reactions lead either to activation or inactivation of a drug. These reactions are further classified as:

i) Oxidation: This reaction involves addition of oxygen / negatively charged radical or removal of hydrogen / positively charged radical. Oxidations are the most important drug metabolizing reactions it occurs mainly in the liver.

Examples – ethyl alcohol, barbiturates, paracetamol, phenytoin, theophylline.

Oxidation Reaction
Oxidation Reaction

ii) Reduction: This reaction involves addition of hydrogen and removal of oxygen. E.g. chloramphenicol , halothane .

iii) Hydrolysis: This is cleavage of drug molecule by taking up of a molecule of water. Hydrolysis occurs in liver , intestine, plasma and other tissues.e.g. acetylcholine, lidocaine, procaine , pethidine.

Hydrolysis Reaction

iv) Cyclization: This is formation of ring structure from a straight chain compound. E.g. proguanil.

v) Decyclization: This is opening up of ring structure of the cyclic drug molecule. E.g. barbiturates, phenytoin .

2. Synthetic Reactions

Synthetic reactions are also called as “conjugation reactions” lead only to inactivation of drug which is easily excreted in urine or bile. The following are the various conjugation reactions.

  • Glucoronide Conjugation: This is the most important synthetic reaction. Compounds with hydroxyl or carboxylic acid group are easily conjugated with glucoronic acid which is derived from glucose. E.g. chloramphenicol, aspirin, morphine, metronidazole. Drug glucoronides excreted in bile can be hydrolyzed by bacteria in the gut.
  • Acetylation: Compounds having amino or hydrazine residues are conjugated with the help of acetyl co-enzyme A. e.g. sulphonamides,isoniazid, PAS.
  • Methylation: The amines and phenols can be methylated.e.g adrenaline, histamine, nicotinic acid.
  • Sulfate Conjugation: The phenolic compounds and steroids are sulfated by sulfokinases. E.g. chloramphenicol, adrenal and sex steroids.
  • Glycine Conjugation: Salicylates and other drugs having carboxylic acid group are conjugated with glycine.
  •  Glutathione Conjugation: Paracetamol.
  • Ribonucleoside / Nucleotide Synthesis: It is important for the activation of many purine and pyrimidine anti-metabolites  used in cancer therapy.

Only few drugs are metabolize by enzyme the drug metabolizing enzymes are-

  • Microsomal: These are located on smooth endoplasmic reticulum, primarily in liver, also in kidney, intestinal mucosa and lungs. E.g. monooxygenases, cytochrome P 450, glucoronyl transferases.
  • Non microsomal: These are present in the cytoplasm and mitochondria of hepatic cells as well as in other tissues in including plasma. E.g. flavoprotein oxidases, esterase’s, amidases, and conjugases.
  • Hofmann Elimination: This refers to inactivation of the drug in the body fluids by spontaneous molecular rearrangement without the agency of any enzyme. E.g. atracurium.
  • Inhibition of Drug Metabolism: One drug may competitively inhibit the metabolism of another if it utilizes the same enzyme or co-factors. Inhibition of drug metabolism occurs in a dose related manner and can precipitate toxicity of the object drug. E.g. propranolol reduces the rate of lignocaine metabolism by decreasing hepatic blood flow.
  • Microsomal Enzyme Induction: Many drugs, insecticides and carcinogens interact with DNA and increase the synthesis of microsomal enzyme protein, specially cytochrome P 450 and glucoronyl transferase. As a result rate of metabolism is increased. Induction involves microsomal enzymes in liver as well as other organs and increases the rate of metabolism by 2-4 folds. Induction takes 4-14 days to reach its peak and is maintained till the inducing agent is being given, there after the enzymes return to their original value over 1-3 weeks.

First Pass Metabolism

This refers to metabolism of a drug during its passage from the site of absorption in to the systemic circulation. All orally administered drugs are exposed to drug metabolizing enzymes in the intestinal wall and liver (where they first reach through the portal vein). First pass metabolism of limited magnitude, can also occur in the skin (transdermally administered drug) and in lungs.The extent of first pass metabolism differs for different drugs.

Attributes of Drugs with High First Pass Metabolism

  • Oral dose is considerably higher than sublingual or parenteral dose.
  • There is marked in individual variation in the oral dose due to differences in the extent of first pass metabolism.

Oral bioavailability is apparently increased in patients with severe liver disease.

Oral bioavailability of a drug is increased if another drug competing with it in first pass metabolism is given concurrently.

e.g. chlorpromazine and propranolol.

Factors Modifying Biotransformation:

Biotransformation of a drug may be modified by the following factors—

  • Inhibitors: Drug metabolizing enzyme can be inhibited by compounds like SKF 525 A. Such compounds decrease the metabolism of a drug. This in turn increases the duration of action.
  • Stimulators: The activity of drug metabolizing enzymes can be increased by certain drugs e.g. in presence of Phenobarbital the metabolism of hexobarbital is increased.
  • Age: Metabolism of drug is poor in young children because of poor development of drug metabolizing enzymes e.g. lack of glucoronyl transferase for the inactivation of chloramphenical in the new born (this produces gray baby syndrome). Gray baby syndrome, in this the baby stopped feeding, vomited, became hypotonic and hypothermic, abdomen distended, respiration became irregular; an ashen gray cyanosis developed in many, followed by cardiovascular collapse and death. Blood lactic acid was raised.
  • Sex: Females have less ability to metabolize drugs.
  • Species: Rabbits metabolize atropine due to the presence of atropinase, human lack this enzyme. So, atropine is toxic to human but non-toxic to rabbits. Genetic Deficiencies in drug metabolizing enzymes can be inherited, e.g. primaquine produces haemolysis in genetic deficiency of the enzyme Glucose 6- phosphate dehydrogenase (G-6-PD).
  • Body temperature: Increase in body temperature increases drug metabolism, where as decrease in body temperature has the opposite effect.

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