Biotransformation

Definition: Chemical alteration of the drug in the body is known as biotransformation.

Sites: Primary sites for drug metabolism are Liver. Others are- kidney, intestine, lungs, skin.
Aims of biotransformation: It is needed to render nonpolar (lipid soluble) compounds polar (lipid insoluble), so that they are
excreted.
Purpose/objectives:
1. Conversion of a pharmacologically active to an inactive substance.
2. Conversion of one pharmacologically active to another active substance- this has the effect of prolonging the drug action. Ex.
Chloroquine- hydroxychloroquine. Codeine- morphine
3. Conversion of pharmacologically inactive to active substance( prodrug). Ex. Levodopa- dopamine. Sulfasalazine- 5-amino salicylic acid
Prodrug
There are some drugs that do not produce any pharmacological effects until they are chemically altered within the body are known as prodrug.
Example:
Prodrug Active form
Levodopa Dopamine
Enalapril Enalaprilat
Prednisone Prednisolone
α methyldopa α methylnorepinephrine
Sulfasalazine 5-amino salicylic acid
Advantages:
1. Being more stable and having more bioavailability.
2. To reduce adverse effects.
Phase/Type of biotransformation:
Phase I/ nonsynthetic / initial phase
Phase II/ synthetic/ conjugation
Phase I reaction: Phase I reaction may result in activation, change in activity or inactivation of parent drug. It consist of-
i) Oxidation
ii) Reduction
iii) Hydrolysis
Criteria:
i) Convert lipophilic molecules into more polar molecules.
ii) Metabolite may be active or inactive.
iii) Phase I reactions generally convert foreign compounds to derivatives that can undergo phase II reaction.
Phase II reactions:
This phase consists of conjugation reactions. Phase II reactions may take place when a drug or phase I metabolite contains a
chemical group such as hydroxyl (-OH), carboxyl(-COOH), amino (-NH2) & is suitable for combining with a natural compound provided by the body
to form readily excreted water soluble polar metabolites. Conjugating agents include glucuronic acid ,glycine, methionine, sulfate & acetyl.
Phase II reactions/conjugations reactions:
i) Glucuronide conjugation. Ex. aspirin, paracetamol, morphine
ii) Sulphate conjugation. Ex. Chloramphenicol
iii) Amino acid or glycine conjugation Ex. Salicylic acid
iv) Acetylation Ex. Isoniazid
v) Methylation Ex. Methyldopa
Criteria:
i) Conjugate with endogenous substrates such as glucuronic acid, amino acid or acetic acid.
ii) Loss of biological activity.
iii)Form more polar highly ionized organic acid, which is easily excreted in urine.
Enzymes responsible for biotransformation:
a) Microsomal enzymes: These enzymes are located in the smooth endoplasmic reticulum mainly of the liver. Microsomal enzymes are
inducible by drugs.Example: Cytochrome P450 containing monooxygenases or mixed function oxidase P450.
b)Non-microsomal enzymes: These are present in the cytoplasm & mitochondria of hepatic cells. These are not inducible by drug.
Example: Esterases, Amidases,Hydrolases
Enzyme induction
The activity or synthesis of microsomal enzymes can be increased by administration of certain drugs and by exposure to various chemicals.
Enzyme inducing drugs: Phenobarbitone, Phenytoin, Diazepam, Carbamazepine, Rifampicin
 Consequences of enzyme induction:
1) Decreased intensity or duration of action of drugs that are inactivated by metabolism. rifampicin + ocp = failure of contraception.
2) Increased intensity of action of drugs that are activated by metabolism. rifampicin + paracetamol= paracetamol toxicity.
3) If the drug induces its own metabolism (autoinduction) then tolerance may develop. Ex. Rifampicin.
Enzyme inhibition
One drug can competitively inhibit the metabolism of another if it utilizes the same enzyme.
Example of enzyme inhibitors-
Isoniazid, Cimetidine, Chloramphenicol, Ciprofloxacin, Erythromycin, Ketoconazole, Metronidazole
Clinical importance: Inhibition of CYP isoenzyme activity is an important source of drug interactions that lead to serious adverse events.
Ex. Metronidazole + warfarin →increase plasma concentration of warfarin→inhibition of coagulation→ risk of haemorrhage.
Factors influencing biotransformation:
Age: Drug metabolism enzymes are not well developed during very early age and become exhausted during old age. So decrease biotransformation of
drugs & increased toxicity.
Nutritional status: There is decreased activity of enzymes of biotransformation in mammals suffering from ca, vit. C & protein deficiency.
Genetic factors: Genetic factors influence enzyme levels in drug metabolism resulting in altered efficacy of drug therapy & adverse drug reactions.
Example: succinylcholine, isoniazid and warfarin shows genetic polymorphism.
Plasma protein binding: Reduces the rate of metabolism.
Excretion
The more rapid excretion, the less is the opportunity for interaction.
Pathological factors: Certain diseases such as hepatitis, hepatic cirrhosis can markedly affect metabolism of drugs.
Enzyme induction & enzyme inhibition: Enzyme inducer & enzyme inhibitors altered the rate of metabolism.
Excretion or elimination of drugs: Excretion means the transportation of unaltered or altered form of drug out of the body.
Major routes:
1. Urine (renal excretion)
2. Bile (hepatobiliary excretion)- conjugated drugs are excreted. Molecular weight more than 300 daltons and polar drugs are excreted.
ex, tetracycline
3. Faeces ( gastrointestinal excretion): ex. Ferrous sulfate, heavy metals
4. Exhaled air ( pulmonary excretion): ex. Gas & volatile liquid ( general anesthetics & alcohol)
Minor routes: Saliva, Sweat,Tear, Breast milk- phenytoin, aspirin,ampicillin,diazepam
The excretion of drugs by kidney involves: Glomerular filtration, Active tubular secretion, Tubular reabsorption
Renal excretion = (Glomerular filtration + Tubular secretion ) – Tubular reabsorption.
Glomerular filtration: It depends on- i)Concentration of drug in the plasma, ii)Molecular size,shape & charge of the drug. iii)Glomerular filtration
rate. Drugs in free form can pass through glomerulus. Charged compounds are filtered at slower rates than neutral. Ex. Protein crosses glomerulus
at a slower rate than dextran. In CCF filtration of a drug is reduced.
Active tubular secretion: A major contribution to urinary excretion of drugs is active tubular secretion. There is active transport of organic acid
bases by two transporters in proximal tubules.
Organic acid transport: penicillin, probenecid, uric acid, salicylates. Organic base transport: thiazides, frusemide, quinine.
Tubular reabsorption: Reabsorption of drug from the lumen of DCT into plasma occurs either by simple diffusion or by active transport.
Changes in urinary pH affect tubular reabsorption of drugs-
Weak bases ionize more & are less reabsorbed in acidic urine.
Weak acids ionize more & are less reabsorbed in alkaline urine.
This principle is utilized for facilitating elimination of the drug in poisoning. Ex. Urine is alkalized in salicylate poisoning.
Prolongation of drug action
1. By prolonging absorption from site of administration:
a) Oral- sustained release tablet, controlled release tablet such preparations prolong the action of drug.
b) Parenteral- The subcutaneous & intramuscular injection of drug in insoluble form (benzathine penicillin) or as oily solution (depot
progestins) prolong absorption.
c) Inclusion of vasoconstrictor with the drug also delays absorption. Ex. Adrenaline with local anesthetics.
2. By increasing plasma protein binding:
Highly plasma protein bound drugs are slowly released in the free active form,e.g-sulfadoxine.
3. By retarding rate of metabolism:
Small chemical modification can markedly affect the rate of metabolism. Ex addition of ethinyl group to estradiol makes it long acting &
suitable as for oral contraceptive. Inhibition of specific enzymes by one drug can prolong the action of another drug. ex. Cilastatin protects the
immune system from degradation in the kidney.
4. By retarding renal excretion: Probenecid prolong the duration of action of penicillin & ampicillin.