- Biotransformation is define as chemical alteration of the drug in the body.
- It is the process of conversion of one form to another form.
- The non-polar lipid soluble compounds are converted into polar (lipid insoluble), so that it is easily excreted.
Site of Biotransformation
- Liver (Primary site)
- Plasma etc.
Why Biotransformation is necessary
- It reduce the toxicity of drugs.
- Biotransformation converted the non-polar to polar.
- Renal and biliary excretion is increased.
Outcomes of Biotransformation
- Most of the drugs are inactive or less active.
- Example: lidocaine, chloramphenicol, paracetamol, ibuprofen, propranolol etc.
- Active drugs to active metabolites
- Many drugs converted to one or more active metabolites; the effect is due to parent drug and active metabolites.
- Activation of active drugs (Prodrug)
- An inactive drug converted to one or more metabolites, such types of drug is called prodrug.
- The advantages of prodrugs are:
- More stable
- Greater Bioavailability
- Less toxicity
|Active drug||Active Metabolites|
Types of biotransformation
- Phase – I / Non-synthetic / Functionalization reaction
- Phase – II / Synthetic / Conjugation
Phase – I reaction
- In this reaction a functional group is generated.
- The metabolites are either active or inactive.
- Phase – I reaction under goes;
- Oxidation is addition of oxygen (negatively charged) or removal of hydrogen (positive charged).
- Oxygen atom into the drug molecules produced unstable intermediate Quinone / Epoxide / Superoxide which then convert to more stable compounds.
- Oxidative reactions are mostly carried out by a group of monooxygenases in the liver.
- In the final step involve CYP (450)haemoprotein, reductase, NADPH and oxygen.
- Types of oxidation reaction
- It is present in endoplasmic reticulum of hepatic cell.
- Oxidation at nitrogen atom
- Oxidation at Sulphur atom
- Chlorpromazine to chlorpromazine sulfoxide
- Cimetidine to cimetidine sulfoxide
- Aliphatic carboxylation
- Salicylic acid to Gentisic acid
- Aromatic hydroxylation
- Dealkylation at oxygen atom
- Phenacetin to paracetamol
- Dealkylation at nitrogen atom
- Amitriptyline to nortriptyline
- Dealkylation at sulphur atom
- 6 thiopurine to mercaptopurine
- Oxidative deamination (monoamine oxidase MAO, diamine oxidase DAO)
- Parathion to paraoxon
- Present in cytoplasm, mitochondria of liver cell, GI tract, plasma, and other tissue.
- Mitochondrial enzymes
- MAO – Oxidative deamination of Adrenaline, 5HT, Tyramine
- Cytoplasmic enzyme
- Dehydrogenases – Alcohol oxidation to Acetaldehyde & Acetic acid.
- Plasma oxidative enzymes – Histaminase, Xanthine oxidase.
- Mitochondrial enzymes
Some important CYP iso-enzymes
- CYP is enzyme
- 1, 2, 3 etc. are the family
- A, B, C etc. are subfamily (amino acid sequence)
- 4, 5 etc. are gene number
- CYP3A4/5 is carried out nearly 50% biotransformation of drugs. It is located in liver, kidney, and intestine.
- It is responsible for fast pass metabolism.
- Substrates: cyclosporine, dapsone, diazepam.
- Inducers: barbiturates, carbamazepine, rifampicin and other anticonvulsant
- Inhibitor: erythromycin, clarithromycin, ketoconazole, Iitraconazole.
- About 20-30% drug metabolism
- Inhibition of this enzyme by quinidine, this fails codeine to morphine conversion, results effect of codeine is lost.
- Inducer – unknown
- Phenytoin, carbamazepine, warfarin, etc. are metabolized.
- Inducers: rifampicin and barbiturates.
- Inhibitor: montelukast, pioglitazone.
- Substrates: diclofenac, losartan.
- Inducer: carbamazepine, rifampicin.
- Inhibitor: fluconazole, fluvoxamine.
- Omeprazole, lansoprazole, phenytoin, diazepam, and propranolol are commonly metabolized.
- About 12-15% of drug metabolism occur.
- Inducers: barbiturates ,rifampicin
- Inhibitor: fluconazole, ticlopidine
- Only few drugs like theophylline, caffeine, paracetamol, and carbamazepine etc. are carried out metabolism.
- Inducers: rifampicin, smoking
- Inhibitor: fluvoxamine
- Substrates: alcohol, halothane
- Inducers: alcoholism
- Inhibitor: disulfiram, 4-methylpyrazole
- Drugs like cimetidine, ranitidine, clozapine are oxidized at their N, P or S atoms by a group of flavin-monooxygenases.
- Location: hepatic endoplasmic reticulum.
- The reductive reactions are exact opposite of oxidation.
- Addition of hydrogen (+ve charged) or removal of oxygen (-ve charged) radical.
- Microsomal Reduction by Monooxygenases need NADPH & cytochrome c reductase.
- Nitro reduction
- Reduction of nitro group proceeds via formation of nitroso and hydroxylamine intermediates to yield amines.
- Example: reduction of Nitrazepam, Nitrazepam to 7-aminometabolites
- Chloramphenicol to aryl amine metabolites.
- AZO reduction
- Reduction· of azo compounds yield primary amines via formation of hydrazo intermediate (-NH-NH-) which undergoes cleavage at N-N bond.
- Example: Prontosil to sulfanilamide
- Cortisone to hydrocortisone
- Non-microsomal reduction
- Chloral hydrate to Trichloro ethanol.
- Nitro reduction
- Drug is split combining with water.
- Ester + water gives Alcohol & Acid in presence of enzyme esterase
- Microsomal hydrolysis
- Pethidine to meperidinic acid
- Non microsomal hydrolysis –Esterases, Amidases & Peptidases
- Atropine to Tropic acid
- Formation of ring structure from a straight chain compound.
- Example: Proguanil
- Opening up of ring structure of the cyclic drug molecule.
- Example: barbiturates, phenytoin
Phase – II reaction
- Phase – II reaction involves conjugation of drug or chemically alter the phase – I metabolites.
- These are derived from carbohydrate or amino acid, to form highly polar ionized organic acid, which are easily excreted in urine and bile.
- Glucuronide conjugation
- Sulfate conjugation
- Glycine conjugation
- Glutathione conjugation
- Ribonucleotide / Ribonucleoside synthesis
- It is carried out by a group of UDP-glucuronosyl transferases (UGTs).
- Compound having hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid which is derived from glucose.
- Diazepam, lorazepam
- Substrates like bilirubin, steroidal hormones and thyroxine also undergoes this pathway.
- Increasing the molecular weight of the drug by glucuronidation which results its excretion in bile.
- Drug glucuronides excreted in bile are hydrolyzed by intestinal microfloral enzymes. The liberated drugs reabsorbed into systemic circulation, this results decrease excretion, increase duration of action.
- Oral contraceptives.
- Acetylation is a metabolic pathway which containing primary amino groups.
- It requires cofactor Ach CoA, and this reaction is responsible by the enzyme N-acetyl transferase.
- Substrates: drugs with amino or hydralazine group.
- Acetyl derivatives of some sulfonamides causes renal toxicity due to decreased water solubility of the metabolites.
- The amines and phenols can be methylated by methyl transferases.
- The endogenous substance is cysteine, methionine.
- Enzyme includes methyl transferase.
- Nicotinic acid
- Dopamine, methyl dopa
- The phenolic compounds and steroids are sulfated by sulfotransferases (SULTs).
- Adrenal and sex steroid
- Drug group: acetyl Co A derivative of carboxylic acid
- catalyzed by Acyl-CoA glycine transferase
- location: mitochondria
- Example: salicylic acid, benzoic acid.
- It is carried out by glutathione-S-transferase (GST) forming a mercapturate.
- Drug groups: epoxides, nitro groups.
- Paracetamol, Ethacrynic acid
- Activation of purine and pyrimidine antimetabolites.
- Example: 6-mercaptopurine.