SUMMARY

Drug Metabolism

Biotransformation (Metabolism)

• Definition: Drug metabolism or biotransformation involves the chemical reactions that convert drugs into other products (metabolites) within the body before and after they have reached their sites of action.
• Hydrophilic Drugs: Most hydrophilic drugs (e.g., streptomycin, neostigmine, pancuronium) undergo little biotransformation and are largely excreted unchanged.
• Mechanisms: Mechanisms of drug metabolism have evolved to protect the body from ingested toxins.
• Primary Sites: The liver is the primary site for drug metabolism, with other sites including the kidney, intestine, lungs, and plasma.

Consequences of Biotransformation

• The biotransformation of drugs may lead to the following outcomes:
  1. Inactivation: Most drugs and their active metabolites are rendered inactive or less active. Examples include:
  • Ibuprofen
  • Paracetamol
  • Lidocaine
  • Chloramphenicol
  • Propranolol and its active metabolite, 4-hydroxypropranolol
  1. Active Metabolite from an Active Drug: Many drugs are partially converted to one or more active metabolites.
  2. Activation of Inactive Drug: Some drugs are inactive and require conversion in the body to one or more active metabolites (known as prodrugs). Advantages of Prodrugs:
  • More stable
  • Better bioavailability
  • Other desirable pharmacokinetic properties
  • Fewer side effects and reduced toxicity
  • Some prodrugs are activated selectively at the site of action.

Active Metabolites from Active Drugs

Table 1: Active Drug and Their Active Metabolites

Prodrugs and Their Active Forms

Table 2: Prodrugs and Corresponding Active Forms

Types of Biotransformation Reactions

Phase I (Nonsynthetic) Reactions:

1. Oxidation
2. Reduction
3. Hydrolysis
4. Cyclization
5. Decyclization

Phase II (Synthetic / Conjugation) Reactions:

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

Drug Metabolizing Enzymes

• Types of Drug Metabolizing Enzymes:
  A. Microsomal Enzymes
  B. Non-Microsomal Enzymes

A. Microsomal Enzymes:

• Location: Found on smooth endoplasmic reticulum (SER), primarily in liver, but also in kidney, intestinal mucosa, and lungs.
• Examples: Monooxygenases, cytochrome P450, epoxide hydrolases.
• Function: Catalyze most oxidations, reductions, hydrolysis, and glucuronide conjugation.

B. Non-Microsomal Enzymes:

• Location: Present in the cytoplasm and mitochondria of hepatic cells and in other tissues, including plasma.
• Examples: Esterases, amidases, some flavoprotein oxidases, and most conjugases.
• Function: Catalyze some oxidations and reductions, many hydrolytic reactions, and all conjugations except glucuronidation.
• Characteristics: Non-microsomal enzymes are not inducible but may exhibit genetic polymorphism (e.g., acetyl transferase, pseudocholinesterase).

Sites of Drug Metabolism

• Hepatic Enzymes:

  • Microsomal enzymes:
  • Oxidation, conjugation
  • Non-microsomal enzymes:
  • Acetylation, sulfation, GSH, alcohol/aldehyde dehydrogenase, hydrolysis, oxidation/reduction

• Extra-Hepatic Enzymes:

  • Microsomal enzymes: Oxidation, conjugation
  • Non-microsomal enzymes: Acetylation, sulfation, hydrolysis, etc.

Phase I Metabolic Reactions

1. Oxidation:

• Definition: Addition of oxygen or removal of hydrogen.
• Importance: Oxidations are the most significant drug metabolizing reactions and are the main process of metabolism.
• Products: Produce unstable superoxides, quinones, intermediates like epoxides.

The Role of Cytochrome P450 (CYP) in Oxidative Reactions

• Definition: Cytochrome P450 enzymes, known as microsomal mixed-function oxidases, are membrane-bound proteins.
• Location: They are present in the smooth endoplasmic reticulum of the liver and other tissues.
• Significance: These enzymes play a crucial role in Phase I biotransformation of drugs.
• Structure: They contain a heme prosthetic group, wherein the heme group consists of iron-porphyrin.
• Function: The oxidizing site in CYP enzymes is the heme center, which converts hydrophobic compounds into hydrophilic or more polar metabolites for excretion.
• CYP450 Binding: Named CYP450 because the iron in its reduced state has a high affinity for carbon monoxide.

Reaction Mechanism:

• General Reaction Description:
  • CYPs catalyze the transfer of one atom of oxygen to a substrate, yielding an oxidized substrate and a molecule of water.
  • Equation: R-H + O2 + NADPH + H^+ → R-OH + H2O + NADP^+

Oxidation Reactions

Types of Oxidation Reactions (9 types)

1. Oxidation at Nitrogen Atom: RNH₂ → RNOH

   • Examples: Chlorpheniramine, Dapsone

2. Oxidation at Sulphur Atom: R-SH2 → R-S=O

   • Examples: Chlorpromazine, Chloramphenicol

3. Aliphatic Hydroxylation:

   • Hydroxyl group added to drug: RCH2CH3 → RCHOHCH3
   • Examples: Salicylic acid to Gentisic acid, Ibuprofen, Tolbutamide, Chlorpropamide

4. Aromatic Hydroxylation:

   • R → R-OH
   • Examples: Acetanilide, Phenytoin, Phenobarbital, Propranolol

5. Dealkylation at Oxygen Atom:

   • ROCH3 → ROH + CH2O
   • Example: Phenacetin to Paracetamol

6. Dealkylation at Nitrogen Atom:

   • RNHCH3 → RNH₂ + CH2O
   • Example: Methamphetamine to Amphetamine

7. Dealkylation at Sulphur Atom:

   • R-SCH3 → RSH + CH2O
   • Example: 6-Methyl mercaptopurine to Mercaptopurine

8. Oxidative Deamination:

   • RCHNH₂ → RCOR + NH3
   • Example: Amphetamine → Phenylacetone

9. Desulfuration:

   • R₁P=S → R₁P=O
   • Example: Parathion to Paraoxon

Reduction Reactions

• Definition: Reduction is the converse of oxidation, with cytochrome P-450 enzymes working in the opposite direction, leading to the reduction of compounds like alcohols and aldehydes.

Types of Reduction Reactions:

1. Nitro Reduction:

   • R-NO2 → R-NH2
   • Examples: Clonazepam and Nitrazepam

2. Keto Reduction:

   • R-CO-R → R-CHOH-R
   • Example: Phenylacetone to 1-Phenyl-2-propanol

3. Azo Reduction:

   • Ar-N=N-Ar' → Ar-NH-NH-Ar' → Ar-NH₂ + H₂N—Ar'
   • Example: Prontosil to Sulfanilamide

Hydrolytic Reactions

• Definition: Hydrolysis is the cleavage of drug molecules through the addition of a molecule of water.
  • Example Reaction: Ester + H₂O → Acid + Alcohol
• Additional Hydrolytic Processes: Amides and polypeptides are hydrolyzed by amidases and peptidases. Epoxide hydrolases facilitate the detoxification of epoxide metabolites generated by CYP oxygenases.
• Locations of Hydrolysis: Occurs in the liver, intestines, plasma, and various tissues.
• Examples of Hydrolyzed Drugs: Choline esters, procaine, lidocaine, procainamide, aspirin, carbamazepine-epoxide, pethidine, and oxytocin.

Cyclization and Decyclization

1. Cyclization: Formation of a ring structure from a straight-chain compound, e.g., proguanil.
2. Decyclization: Opening of the ring structure of cyclic drug molecules, e.g., barbiturates and phenytoin (generally a minor pathway).

Phase II Reactions (Conjugation)

• Definition: Phase II reactions are the primary detoxification processes. They follow Phase I reactions and typically occur with the products derived from Phase I reactions.
• Mechanism: In these reactions, suitable moieties such as glucuronic acid, glutathione, sulfate, glycine, etc., conjugate with the metabolites from Phase I reactions.
• Characteristics: Termed conjugation reactions, as the metabolites combine with large, strongly polar moieties, facilitating excretion.
• Enzymes Involved: Various transferase enzymes, including UDP-glucuronosyl transferases, sulfotransferases, glutathione transferases.

1. Glucuronide Conjugation:

• Significance: Most important synthetic reaction, facilitated by a group of UDP-glucuronosyl transferases (UGTs).
• Process: Compounds with hydroxyl or carboxylic acid groups conjugate efficiently with glucuronic acid (derived from glucose).
• Outcome: Increases the molecular weight of drugs, favoring their excretion in bile.

2. Acetylation:

• Process: Compounds with amino or hydrazine groups are conjugated with acetyl coenzyme A.
• Examples: Sulfonamides, isoniazid, PAS, dapsone, hydralazine, clonazepam, procainamide.
• Genetic Factors: Multiple genes control N-acetyl transferases (NATs), and the rate of acetylation exhibits genetic polymorphism (slow and fast acetylators).

3. Methylation:

• Process: Amines and phenols are methylated by methyl transferases (MT), using methionine and cysteine as methyl donors.
• Examples: Adrenaline, histamine, nicotinic acid, methyldopa, captopril, mercaptopurine.
• Enzyme: COMT - Catechol-O-methyl transferase.

4. Sulfate Conjugation:

• Significance: Phenolic compounds and steroids are sulfated by sulfotransferases (SULTs).
• Examples: Chloramphenicol, methyldopa, adrenal, and sex steroids.

5. Glycine Conjugation:

• Overview: Salicylates, nicotinic acid, and other drugs with carboxylic acid groups are conjugated with glycine; however, this is not a major metabolic pathway.

6. Glutathione Conjugation:

• Process: Conducted by glutathione-S-transferase (GST), forming mercapturates.
• Role: Typically a minor pathway but crucial for inactivating highly reactive quinone or epoxide intermediates produced during the metabolism of certain drugs (e.g., paracetamol).
• Implications: In cases of overproduction of such intermediates (e.g., poisoning or enzyme induction), glutathione levels may be insufficient, leading to the formation of toxic adducts with tissue components and resultant tissue damage.

7. Ribonucleoside/Nucleotide Synthesis:

• Significance: Important for activating many purine and pyrimidine antimetabolites used in cancer therapy.
• Example: Metabolic activation of 5-fluorouracil to 5-FdUMP (5-Fluoro deoxyuridine monophosphate).

Simultaneous and Sequential Metabolism

• Description: Drugs may undergo simultaneous and/or sequential metabolism through Phase I and Phase II reactions.

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