Pharmacology

Biotransformation

Definition

  • 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)
  • Kidney
  • Lungs
  • Intestine
  • 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

  1. Inactivation
    • Most of the drugs are inactive or less active.
    • Example: lidocaine, chloramphenicol, paracetamol, ibuprofen, propranolol etc.
  2. Active drugs to active metabolites
    • Many drugs converted to one or more active metabolites; the effect is due to parent drug and active metabolites.
  3. 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 drugActive Metabolites
AllopurinolAlloxanthine
DiazepamOxazepam
ImipramineDesipramine
CodeineMorphine
DigitoxinDigoxin
PrimidonePhenobarbitone
Chloral hydrateTrichloroethanol
AmitriptylineNortriptyline
Active drugs to active metabolites
ProdrugActive form
LevodopaDopamine
EnalaprilEnalaprilat
PrednisonePrednisolone
Sulfasalazine5-aminosalicylic acid
FluorouracilFluorouridine monophosphate
AcyclovirAcyclovir triphosphate
BacampicillinAmpicillin 
Activation of active drugs (Prodrug)

Types of biotransformation

  1. Phase – I / Non-synthetic / Functionalization reaction
  2. 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
    • Reduction
    • Hydrolysis
    • Cyclization
    • Decyclization

Oxidation

  • 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
    1. Microsomal
    2. Non-microsomal

Microsomal oxidation

  • It is present in endoplasmic reticulum of hepatic cell.

Types

  1. Oxidation at nitrogen atom
    • Chlorpheniramine
    • Dapsone
    • Meperidine
  2. Oxidation at Sulphur atom
    • Chlorpromazine to chlorpromazine sulfoxide
    • Cimetidine to cimetidine sulfoxide
  3. Aliphatic carboxylation
    • Salicylic acid to Gentisic acid
    • Ibuprofen
    • Tolbutamide
  4. Aromatic hydroxylation
    • Phenytoin
    • Phenobarbitone
    • Propranolol
  5. Dealkylation at oxygen atom
    • Phenacetin to paracetamol
  6. Dealkylation at nitrogen atom
    • Amitriptyline to nortriptyline
  7. Dealkylation at sulphur atom
    • 6 thiopurine to mercaptopurine
  8. Oxidative deamination (monoamine oxidase MAO, diamine oxidase DAO)
    • Amphetamine
    • Phenylethylamine
    • Epinephrine
  9. Desulfuration
    • Parathion to paraoxon

Non-microsomal oxidation

  • Present in cytoplasm, mitochondria of liver cell, GI tract, plasma, and other tissue.
    1. Mitochondrial enzymes
      • MAO – Oxidative deamination of Adrenaline, 5HT, Tyramine
    2. Cytoplasmic enzyme
      • Dehydrogenases – Alcohol oxidation to Acetaldehyde & Acetic acid.
    3. Plasma
      • Plasma oxidative enzymes – Histaminase, Xanthine oxidase.

Some important CYP iso-enzymes

CYP3A4/5

  • 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.

CYP2D6

  • 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

CYP2C8

  • Phenytoin, carbamazepine, warfarin, etc. are metabolized.
  • Inducers: rifampicin and barbiturates.
  • Inhibitor: montelukast, pioglitazone.

CYP2C9

  • Substrates: diclofenac, losartan.
  • Inducer: carbamazepine, rifampicin.
  • Inhibitor: fluconazole, fluvoxamine.

CYP2C19

  • Omeprazole, lansoprazole, phenytoin, diazepam, and propranolol are commonly metabolized.
  • About 12-15% of drug metabolism occur.
  • Inducers: barbiturates ,rifampicin
  • Inhibitor: fluconazole, ticlopidine

CYP1A1/2

  • Only few drugs like theophylline, caffeine, paracetamol, and carbamazepine etc. are carried out metabolism.
  • Inducers: rifampicin, smoking
  • Inhibitor: fluvoxamine

CYP2E1

  • Substrates: alcohol, halothane
  • Inducers: alcoholism
  • Inhibitor: disulfiram, 4-methylpyrazole

Flavin monooxygenase  

  • Drugs like cimetidine, ranitidine, clozapine are oxidized at their N, P or S atoms by a group of flavin-monooxygenases.
  • Location: hepatic endoplasmic reticulum.

Reduction

  • 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.
    1. 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.
    2. 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
    3. Ketoreduction
      • Cortisone to hydrocortisone 
      • Non-microsomal reduction
      • Chloral hydrate to Trichloro ethanol.

Hydrolysis

  • 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

Cyclization

  • Formation of ring structure from a straight chain compound.
  • Example: Proguanil

Decyclization

  • 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.
    1. Glucuronide conjugation
    2. Acetylation
    3. Methylation
    4. Sulfate conjugation
    5. Glycine conjugation
    6. Glutathione conjugation
    7. Ribonucleotide / Ribonucleoside synthesis

Glucuronide conjugation

  • 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.
  • Example:
    • Chloramphenicol
    • Aspirin
    • Diazepam, lorazepam
    • Paracetamol
    • Morphine
    • Metronidazole
  • 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.
  • Example:
    • Phenolphthalein
    • Oral contraceptives.

Acetylation

  • 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.
  • Example:
    • Isoniazid
    • PAS
    • Dapsone
    • Hydralazine
    • Clonazepam
    • Sulfonamide
    • Procainamide
  • Acetyl derivatives of some sulfonamides causes renal toxicity due to decreased water solubility of the metabolites.

Methylation

  • The amines and phenols can be methylated by methyl transferases.
  • The endogenous substance is cysteine, methionine.
  • Enzyme includes methyl transferase.
  • Example
    • Histamine
    • Nicotinic acid
    • Dopamine, methyl dopa
    • Captopril

Sulfate conjugation

  • The phenolic compounds and steroids are sulfated by sulfotransferases (SULTs).
  • Example:
    • Methyldopa
    • Chloramphenicol
    • Adrenal and sex steroid

Glycine conjugation

  • Drug group: acetyl Co A derivative of carboxylic acid
  • catalyzed by Acyl-CoA glycine transferase
  • location: mitochondria
  • Example: salicylic acid, benzoic acid.

Glutathione conjugation

  • It is carried out by glutathione-S-transferase (GST) forming a mercapturate.
  • Drug groups: epoxides, nitro groups.
  • Example:
    • Paracetamol, Ethacrynic acid

Ribonucleoside/nucleotide synthesis

  • Activation of purine and pyrimidine antimetabolites.
  • Example: 6-mercaptopurine.

Hello! My name is Smrutiranjan Dash, a pharmacy professional. belonging from, Bargarh, Odisha. I have acquired Master degree in Pharmacy (Pharmacology) form B.P.U.T, Rourkela, Odisha. Currently I am working as an Assistant Professor at The pharmaceutical college, Barpali.

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