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Factors affecting Biotransformation

Biotransformation is significantly affected by a number of factors, these include:

1. Enzyme Induction:

When drugs given over prolonged period of time, upregulation of enzymes takes place. Most of the time cytochrome P450 is involved leading to increased synthesis of new enzymes. The rate of metabolism increases as enzyme induction takes place. The drugs which bring about these changes are known as enzyme inducers. Some examples include anticonvulsants like phenytoin, carbomycin and chronic alcoholism. Others include various sedatives, hypnotics, tranquilizers and insecticides.

When drugs are taken together, sometimes drugs acting as enzyme inducers for others cause increased metabolism of themselves, which is known as autometabolism. Example includes artemether and carbamazepine when taken together.

Enzyme induction is brought about by gene transcription, which is enhanced. Enzyme induction leads to a decreased levels of the parent dug and increased levels of metabolites. Sometimes toxic metabolites are also produced. The rate of reaction increases and more quicker conversion of parent drug takes place.

Drugs following first pass metabolism, have decreased bioavailability.

Significance:

Care should be taken when enzyme inducers are given, Especially when two drugs are given together, drug-drug interaction might occur, leading to therapeutic failure.

  1. Rifampicin is an enzyme inducer. If it is taken by female patients taking contraceptives, decreased therapeutic effect might occur, leading to pregnancy. Therefore, the dose should be increased.
  2. Phenobarbitone is used in seizures and epilepsy. It is also an enzyme inducer. If it is administered to patients taking warfarin, therapeutic failure might occur, leading to increased bleeding tendency.

Some enzyme inducers include:

  1. Ethchlorvynol enhances metabolites of warfarin
  2. Phenytoin enhances metabolism of cortisol and digitoxin
  3. Rifampicin increases metabolism of digitoxin
  4. Barbiturates
  5. Chloral hydrate
  6. Erythromycin

Drugs which are significantly affected by enzyme induction include:

  1. Phenytoin
  2. Warfarin
  3. Tolbutamide
  4. Imipramine
  5. Oral contraceptives
  6. Chloramphenicol
  7. Doxycycline
  8. Theophylline
  9. Griseofulvin
  10. Phenylbutazone
Consequencs of Microsomal Enzyme Induction
  1. Decreased intensity and duration of action of drugs e.g. failure of contraceptives
  2. Increased intensity of action of drugs activated by metabolism. E.g. acute paracetamol toxicity is due to one of its metabolites.
  3. If drug induces its own metabolism e.g. cicobarbitone it develops tolerance so effects are not produced.
  4. Precipitation of acute intermittent porphyria. Enzyme induction might increase porphyrin synthesis.
  5. Intermittent use of an inducer might interfere adjustment of dose of another drug e.g. oral anti coagulants, oral hypoglycemic, antiepileptics and antihypertensives.
Auto induction

The phenomenon in which a drug induces metabolism of other drugs as well as its own. E.g. carbamazepine-antiepileptic.

2. Enzyme Inhibition

The process in which  drug metabolizing capacity of cytochrome is decreased is known as enzyme inhibition. The rate of metabolism is decreased. Drugs bringing about these changes are known as enzyme inhibitors. Examples include ketoconazole- antifungal drug, cimetidine and verapamil- calcium channel blocker.

Enzyme inhibition is a rapidly occurring process, most critical for the drugs having a large therapeutic index. Competition for the active sites takes place between the enzymes and the given drugs. When enzyme inhibitor attaches, less metabolism occurs. As rate of metabolism is decreased, plasma levels of parent drug are increased while that of metabolites are low. Serious drug-drug interactions might occur, as the plasma half life is also increased.

Sulfonamides decrease the metabolism of phenytoin so that its blood levels become toxic. Cimetidine decreases the metabolism of propanolol leading to enhanced bradycardia. Metabolism of tolbutamide is inhibited by phenylbutazone or coumarins, leading to prolonged hypoglycemia. Oral contraceptives inhibit metabolism of antipyrine.

3. Presystemic Metabolism/First pass effect/Route of Administration

Drugs following first pass metabolism have decreased bioavailability. Most of the drugs are metabolized within the liver. Changing the route of administration might change the first pass metabolism.

Propanolol is 80% metabolized before reaching systemic circulation.

4. Genetic Variations:

Inter individual variations might occur, as drugs behave differently in different individuals due to genetic variations resulting in absent or malformed enzymes due to absent or malformed genes. Mostly non microsomal enzyme show genetic variations. Examples include succinyl choline, which is a skeletal muscle relaxant. It is metabolized by pseudocholine esterase. Some people lack this enzyme, due to which lack of metabolism of succinyl choline might occur. When administered in those individuals, prolonged apnea might result. Different groups of populations might be classified as fast metabolizers and poor metabolizers of drugs. For certain drugs, like isoniazid, fast acetylators as well as slow acetylators are present. Fast acetylators cause rapid acetylation, while poor metabolizers metabolize less. Hepatic acetyl transferrase catalyzes acetylation. Slow acetylation might occur due to genetic malformation leading to decreased production.

Fast metabolism may lead to hepatotoxicity while poor metabolism might result in peripheral neuropathy. Absence of catalase may lead to achalasia, while G6PD deficiency predisposes erythrocytes to hemolysis as a result of oxidative stress imposed by some commonly used drugs.

5. Species Differences

Species differences are most established in animals. Some metabolize drugs rapidly. Rats and rabbits metabolize drugs more efficiently than humans. Certain species of rabbits feed on Belladonna, and have atropinase to tolerate the effects of atropine. Research on humans is still going on. Asians, Orientals, blacks and whites might have different drug metabolizing capacity. Examples include difference in drug metabolizing capacity of certain anti malarial, amongst the Eskimos and the Asians. Eskimos may metabolize drugs more efficiently than the Asians.

6. Exposure to Pollutants from Environment or Industry

Cigarette smokers might act as enzyme inducers. Chronic alcoholism might lead to enzyme induction as well. Similarly, pesticides or insecticides may act as enzyme inducers.

In hot and humid climate biotransformation is decreased and vice versa. At high altitude, decreased biotransformation occurs due to decreased oxygen leading to decreased oxidation of drugs.

7. Age

Age plays a very important role. Extreme age groups (very young and very old) behave almost the same. Drug metabolizing enzyme develop early but their capacity is low. Thus the rate of metabolism is infants is very low. Care should be taken in administering drugs in younger patients. True development of enzyme occurs in one to two months.

Chloramphenicol (antimicrobial drug) when administered in infant, does not have great efficacy. Toxic effects in the form of grey baby syndrome might occur. The baby may be cyanosed, hypothermic, flaccid and grey in color. Shock and even death might occur if toxic levels get accumulated.

Diazepam (sedative hypnotic) may result in floppy baby syndrome in which flaccidity of the baby is seen.

In elderly, most processes slow down which leads to decreased metabolism. Shrinkage of organs occurs as well along with decreased liver functions and decreased blood flow through the liver. All these factors decrease the metabolism. Old people are usually taking multiple drugs, so are more prone. The drug doses should be decreased in the elderly.

8. Sex

Male have a higher BMR as compared to the females, thus can metabolize drugs more efficiently, e.g. salicylates (others might include ethanol, propanolol, benzodiazepines). Females, during pregnancy, have an increased rate of metabolism. Thus, the drug dose has to be increased. After the pregnancy is over, the dosage is decreased back to normal levels. Example includes phenytoin, whose dose has to be increased during pregnancy (specially second and third trimester).

9. Drug-Drug Interaction

Toxic effects might result when drug combinations act as enzyme inhibitors and inducers. The dose has to be adjusted accordingly.

10. Nutrition

Malnutrition may also effect biotransformation. Depletion of amino acids and glycine may affect drug metabolizing capacity, especially during the phase II, which depends on the food stores. Synthesis of microsomal enzymes depend on nutritional status.

11. Pathological Conditions

Most of the drugs are metabolized in the liver, any disease of which (cirrhosis, viral hepatitis, drugs induced hepatitis, hepatocarcinoma) may affect and slow down the metabolizing capacity. Jaundice depresses glucuronic acid conjugation and oxidative function of liver microsomes.

Cardiovascular diseases, although have no direct effect, decrease the blood flow, which may slow down biotransformation of drugs like isoniazid, morphine and propanolol. Similarly pulmonary conditions may decrease biotransformation. Procaine and procainamide hydrolysis is impaired.

Hypothyroidism increases drug metabolizing capacity (increased half life of antipyrine, digoxin, methimazole, practolol) while hyperthyroidism decreases it.   

12. Circadian rhythm

The rate of hepatic metabolism of certain drugs follow diurnal rhythm in rats and mice. This may be true in humans as well.

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