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Biotransformation means chemical change of a drug within a living organism. Drugs are foreign substances to the body. So body tries to get rid of them subjecting to various mechanisms.

After absorption, drugs could undergo three possible fates:

  • Excreted unchanged.
  • Metabolized by enzymes.
  • Spontaneously changed into other substances because of appropriate pH of body fluids.

Biotransformation makes non-polar (lipid soluble) compounds to polar (lipid insoluble) substances so that they are not reabsorbed in the renal tubules and are excreted. The primary site for drug Biotransformation is liver. Other sites are kidney, intestine, lungs, and plasma. Biotransformation of drugs may lead to the following:

  • Inactivation of drugs such as propranolol, morphine, etc.
  • Formation of active metabolite from an active drug such as imipramine to desipramine; trimethadione to dimethadione. In this case, effect observed is due to the parent drug as well as active metabolite.
  • Formation of active metabolite from inactive drug. Such a drug is called prodrug. Its effect is then due to its active metabolite. Example is levodopa to dopamine.

Enzymes for Drug Biotransformation

Drug metabolizing enzymes are categorized into 2 groups:

  • Microsomal enzymes
  • Non-microsomal enzymes

Microsomal Enzymes

Microsomal enzymes are mainly present in the smooth surfaced endoplasmic reticulum of the liver. Main enzymes are mixed function oxidases and cytochrome P-450 (haem thiolate proteins). About 50 cytochrome P-450s are functionally active in human beings. These are categorized into families and sub-families.

Term CYP (cytochrome P-450 monooxygenases) is used for their identification. About 8—10 isomers of CYP1, CYP2 and CYP3 families are associated in the majority of all drug metabolism reactions in human beings.

Microsomal enzymes are involved primarily with phase-I oxidation and reduction reactions. One exception to this is the involvement of microsomal enzymes system to carry out glucuronide acid conjugation, a phase-TI synthetic reaction.

Non-micrasomal Enzymes

These enzymes are present in plasma, cytoplasm, mitochondria of hepatic cells and other tissues. These enzymes are involved in all phase—IT reactions (except glucuronide conjugation), certain oxidation, reduction and hydrolytic reactions.

Biotransformation reactions are of two types:

Phase—I non-synthetic reactions:

In this case, the metabolite may be active or inactive. It includes following reactions:

i. Oxidation

ii. Reduction

iii. Hydrolysis

These reactions introduce polar groups to drugs such as hydroxyl, amino, sulfhydryl and carboxy. Due to this, drugs are made water soluble and pharmacologically less active.

Oxidation in biotransformation: It is the most significant and important drug metabolizing reaction. Oxidation is carried out by microsomal “mixed function oxidase”(cytochrome P-450, NADPH, and haemoprotein enzymes) and nonmicrosomal oxidases (alcohol dehydrogenase, aldehyde dehydrogenase, diamine oxidase, monoamine oxidase and xanthine oxidase enzymes) in the liver.

Oxidative reactions are hydroxylation, oxidation, deamination and dealkylation. Alcohol, barbiturates, diazepam, theophylline, morphine; paracetamol, steroids, etc. are metabolized by oxidative reactions in biotransformation.

Reduction in biotransformation: It is a reaction which is opposite to oxidation. It is very less common. Some of the drugs which are metabolized by this reaction are chloralhydrate, warfarin, halothane, chloramphenicol, naloxone and prednisone.

Hydrolysis in biotransformation: It occurs in plasma, liver, intestines and other tissues. It is carried out by esterases (e.g. plasma cholinesterase) or amidases. During this reaction, drug molecule is broken down into its two components. Examples are pethidine, cholinesters, procaine, procainamide, and lidocaine.

Conjugated metabolites may reach to intestine through the bile. They may be hydrolysed by the enzymes produced by intestinal organisms. During this reaction, free drug is liberated which is reabsorbed (enterohepatic circulation).

Cyclization in biotransformation: In this reaction, a straight chain compound is converted to ring structure such as proguanil.

Decyclization in biotransformation: In this reaction, ring structure of the cyclic drug molecule opens up, e.g. phenytoin, barbiturates.

Phase-II synthetic (conjugation) reactions: These reactions mostly give rise to inactive metabolites. There occurs conjugation of the drug or its phase-I metabolite with an endogenous substance. The later is derived from carbohydrate or amino acid. This reaction leads to the formation of a polar, highly ionized organic acid which is easily excreted in urine or bile.

Various synthetic reactions in biotransformation are:

Glucuronide conjugation: Drugs with a hydroxyl or carboxylic acid group (e.g. aspirin, phenacetin, chloramphenicol, morphine, metronidazole) and endogenous substances like steroids, bilirubin and thyroxine are conjugated with glucuronic acid which is derived from glucose. It is the most important synthetic reaction.

Glycine conjugation: Compounds having carboxylic group such as salicylates are conjugated with glycine.

Glutathione conjugation: Certain drugs, e.g. paracetamol give rise to highly reactive quinone or epoxide intermediates during metabolism, which are inactivated by glutathione conjugation.

Acetylation: Drugs with amino or hydrazine residues (e.g. sulfonamides, hydralazine, PAS, isoniazid) are acetylated with the help of acetyl coenzyme-A. Rate of acetylation of these drugs is genetically controlled (slow and fast acetylators).

Methylation: The amines and phenols (e.g. adrenaline, histamine, and nicotinic acid) undergo methylation. The endogenous methyl group for this reaction is derived from methionine and cysteine.

Sulfate conjugation: The phenolic compounds and steroids (e.g. chloramphenicol, adrenal and sex steroids) undergo sulfate conjugation by sulfokinases.

Ribonucleoside/ nucleotide synthesis: It plays an important role in the activation of purine and pyrimidine antimetabolites used in cancer therapy.

First-pass effect: On oral administration, a drug has to pass through the gut, gut wall and liver before reaching the systemic circulation. Some drugs may undergo substantial presystemic metabolism during their passage through these organs. This is called “first-pass effect”. This is not seen when the same drug is given parenterally. First-pass effect consists of:

(a) intestinal first pass effect

(b) hepatic first-pass effect.

a. Intestinal first-pass effect: Drugs may be metabolized by gastric acid, digestive — enzymes or by enzymes in gut wall (e.g. catecholamine).

b. Hepatic first-pass effect: If a drug is rapidly metabolized in the liver, very little or no quantity of the orally administered drug reaches the systemic circulation. So to have desired therapeutic effect the drug has to be given either parenterally or orally in very large doses. Some drugs (e.g. propranolol, imipramine) give rise to active metabolites during hepatic biotransformation. These drugs can be given orally.

The bio availability of drugs, which undergo extensive first-pass effect, may vary widely by number of factors. It may be increased and cause drug toxicity in case of hepatic disease, hepatic enzyme inhibition and saturation of metabolizing enzymes while it may be decreased in case of hepatic enzyme induction. Some of the drugs which undergo extensive first pass hepatic metabolism or biotransformation are sex hormones, morphine, labetalol, verapamil, terbutaline, lignocaine.

Inhibition of drug biotransformation: Drug can inhibit metabolizing enzyme activity competitively if it utilizes the same enzyme or cofactors. Often enzyme inhibition produces undesirable drug-drug interactions. However, sometime specific enzyme inhibitors are used for therapeutic purpose, e.g. allopurinol, MAO inhibitors, disulfiram, CHE inhibitors, captopril, etc. Some other clinically important examples are:

  • Cimetidine inhibits biotransformation of propranolol, theophylline and lidocaine.
  • Isoniazid, warfarin, chloramphenicol inhibit the metabolism of phenytoin.
  • Ethanol inhibits methanol biotransformation.
  • Metronidazole and chiorpropamide interfere with alcohol biotransformation.

Microsomal enzyme induction; On repeated administration, certain drugs stimulate the synthesis of microsomal metabolizing enzymes (generally mixed function oxidase enzymes and rarely conjugates). Drugs or chemicals which induce enzymes are called enzyme inducers. Some important enzyme inducers are ethanol, barbiturates, rifampicin, griseofulvin, tobacco, phenytoin, carbarnazepine, etc.

Drugs, whose biotransformation is significantly affected by enzyme induction are phenytoin, warfarin, imipramine, tolbutamide, doxicycline, griseofulvin, oral contraceptives, chloramphenicol, phenylbutazone, and theophylline.

  • Clinical significance of enzyme induction:
  • Development of tolerance (e.g. alcohol, barbiturates), if the drug induces its own biotransformation.
  • Reduction in some normal body constituents, e.g. adrenal steroids, bilirubin, sex hormones, vitamin D.
  • Decreased pharmacological actions of a second drug due to enzyme induction by the first drug, e.g. failure of contraception with oral contraceptives.
  • Increased drug toxicity, e.g. paracetamol, DDT, benzpyrene.
  • Difficulty in dose adjustment of a drug prescribed on regular basis (e.g. oral anticoagulants, oral hypoglycaemics, antiepileptics, antihypertensives) along with intermittent use of an inducer drug.
  • Since enzyme induction increases porphyrin synthesis, an acute intermittent porphyria attack may be precipitated.

Possible uses of enzyme induction:

  1. Phenobarbitone is useful in congenital non-haemolytic jaundice because it causes rapid clearance of jaundice.
  2. Phenytoin may reduce the manifestations of Cushing’s syndrome.
  3. Chronic poisoning.
  4. Liver disease.

There are a number of factors which affect the biotransformation of a drug such as:

a. At the extreme of life (old people and children) the rate of drug biotransformation is slow. So the drug tends to produce greater and more prolonged effects.

b. In human beings, sex dependent variations in drug metabolism or biotransformation are less important. However, males may metabolize salicylates, benzodiazepines and oestrogens quicker than females.

c. Genetic factors and environment such as diet, weight, race, body temperature and specific genetic variation may influence the biotransformation of drugs.

d. Many drugs may affect the biotransformation of other drugs either by enzyme induction (acceleration) or enzyme inhibition (delay).

e. Drug metabolic processes are inhibited in malnourished individuals as well as in patients with hepatic diseases (e.g. alcoholic hepatitis, biliary cirrhosis, viral hepatitis, and cancer liver). Oxidation reactions are affected the most because they are rate limiting. However, conjugation reactions are well preserved as they are less rapidly saturated.

f. Hepatic metabolic efficiency or its Biotransformation is impaired in congestive heart failure because it limits blood flow to the liver. It is enhanced in patients suffering from thyrotoxicosis. However, it is decreased in hypothyroidism and the half lives of practolol, digoxin and methimazole are increased.



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