Define bio transformation. explain the various mechanism of drug metabolism with examples from KDT using buzz words for university exam final LAQ i should have to score without losing a mark. make a pictoral diagram

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A clear educational pharmacology flowchart diagram of drug biotransformation for a university exam: lipophilic drug in center, Phase I functionalization with oxidation reduction hydrolysis and cytochrome P450, Phase II conjugation with glucuronide sulfate acetyl methyl glutathione, resulting water-soluble metabolite and renal or biliary excretion. Include a side branch showing direct Phase II and a warning that Phase I can form active or toxic metabolites.

Drug Biotransformation / Drug Metabolism

Definition

Biotransformation is the enzymatic chemical alteration of a drug (xenobiotic) within the body, usually converting a lipid-soluble, non-polar drug into a more polar, water-soluble metabolite that can be eliminated through urine or bile.

Exam buzz words:
Enzymatic conversion - lipophilic to hydrophilic - functionalization - conjugation - detoxification - bioinactivation - active/toxic metabolite - renal/biliary excretion.

It does not always mean inactivation. Metabolism may produce:

Inactive metabolite: chloramphenicol

Active metabolite: diazepam → desmethyldiazepam

Toxic metabolite: paracetamol → NAPQI

Active drug from prodrug: enalapril → enalaprilat; codeine → morphine

The principal organ is the liver, especially the smooth endoplasmic reticulum (microsomal enzymes) of hepatocytes. Other sites: intestinal mucosa, kidney, lungs, plasma, skin, and brain. Lipophilic drugs would otherwise be reabsorbed from renal tubules and persist in the body. Katzung's Basic & Clinical Pharmacology, 16th ed., p. 93.

Pictorial Diagram: Overall Pathway

Write this flowchart in the exam

                     LIPID-SOLUBLE DRUG
                           │
                           │  (may be directly excreted if already polar)
                           ▼
         ┌───────────────────────────────────────────┐
         │ PHASE I: FUNCTIONALIZATION REACTIONS       │
         │ Oxidation / Reduction / Hydrolysis         │
         │ Introduces or unmasks: -OH, -NH2, -SH, -COOH│
         └───────────────────────────────────────────┘
                           │
          ┌────────────────┼───────────────────┐
          │                │                   │
          ▼                ▼                   ▼
   Inactive metabolite  Active metabolite   Reactive/toxic
          │              e.g., codeine      metabolite
          │              → morphine          e.g., NAPQI
          ▼
  Excretion if sufficiently polar
          │
          ▼
         OR
          │
          ▼
         ┌───────────────────────────────────────────┐
         │ PHASE II: CONJUGATION / SYNTHETIC REACTIONS│
         │ Glucuronidation, sulfation, acetylation,   │
         │ methylation, glutathione, amino-acid       │
         └───────────────────────────────────────────┘
                           │
                           ▼
       HIGHLY POLAR, WATER-SOLUBLE CONJUGATE
                           │
                           ▼
                  URINE / BILE / FECES

Important point: A drug need not undergo Phase I before Phase II. Drugs having groups such as -OH, -NH₂, or -COOH may undergo direct conjugation. Example: morphine and lorazepam undergo direct glucuronidation. Also, Phase II can occasionally precede Phase I, as with isoniazid. Katzung's Basic & Clinical Pharmacology, 16th ed., p. 93.

Mechanisms of Drug Metabolism

Classification at a Glance

Type	Reactions	Main site / enzymes	Main result
Phase I	Oxidation, reduction, hydrolysis	Mainly microsomal CYP450 system	Functional group introduced/unmasked
Phase II	Conjugation / synthetic reactions	Microsomal or cytosolic transferases	Highly polar conjugate formed
Microsomal metabolism	Mostly oxidation, glucuronidation	Smooth ER of liver	Inducible; inhibited; subject to genetic polymorphism
Non-microsomal metabolism	Hydrolysis, acetylation, sulfation, methylation etc.	Cytoplasm, mitochondria, plasma, tissues	Usually not induced by drugs

I. Phase I Reactions: Functionalization Reactions

Definition

These reactions introduce or expose a polar functional group such as:

-OH       -NH2       -SH       -COOH

They generally make a drug more polar and prepare it for Phase II conjugation.

Main reactions

PHASE I = OXIDATION + REDUCTION + HYDROLYSIS

Most Phase I oxidation occurs through the microsomal cytochrome P450 mixed-function oxidase system.

A. Oxidation

1. Cytochrome P450-dependent microsomal oxidation

This is the commonest mechanism of drug metabolism.

Location: Smooth endoplasmic reticulum of hepatocytes, called the microsomal fraction.

Components of CYP450 mixed-function oxidase system

NADPH
  │
  ▼
NADPH-CYP450 reductase
  │
  ▼
Cytochrome P450 (haemoprotein)
  │
  ▼
O2 + Drug (RH)
  │
  ▼
Oxidized drug (ROH) + H2O

General reaction

RH + O2 + NADPH + H+
          CYP450
────────────────────→ ROH + H2O + NADP+

Why called mixed-function oxidase / monooxygenase?
One atom of oxygen is incorporated into the drug, while the other atom is reduced to water.

Important CYP450 isoenzymes

Isoenzyme	High-yield examples of drugs metabolized
CYP3A4/5	Midazolam, cyclosporine, statins, erythromycin, many drugs
CYP2D6	Codeine, metoprolol, tricyclic antidepressants
CYP2C9	Warfarin, phenytoin, NSAIDs
CYP2C19	Diazepam, omeprazole, clopidogrel
CYP1A2	Theophylline, caffeine
CYP2E1	Ethanol, paracetamol bioactivation

Types of oxidative reactions with examples

Oxidative reaction	Example
Aromatic hydroxylation	Phenytoin, warfarin, propranolol
Aliphatic hydroxylation	Pentobarbital, ibuprofen
N-dealkylation	Diazepam, imipramine, morphine derivatives
O-dealkylation	Codeine → morphine
S-dealkylation	Methitural
N-oxidation	Nicotine, imipramine
S-oxidation	Chlorpromazine, cimetidine
Oxidative deamination	Amphetamine
Desulfuration	Thiopental; parathion → paraoxon
Epoxidation	Carbamazepine; aromatic hydrocarbons

Katzung lists aromatic and aliphatic hydroxylation, epoxidation, N/O/S-dealkylation, N-oxidation, S-oxidation, deamination, desulfuration, and dechlorination among CYP450-dependent oxidations. Katzung's Basic & Clinical Pharmacology, 16th ed., Chapter 4.

High-scoring examples

Codeine ──CYP2D6 O-dealkylation──► Morphine (active metabolite)

Diazepam ──CYP3A4 N-dealkylation / hydroxylation──► Active metabolites
         ──glucuronidation──► Excretion

Paracetamol ──CYP2E1──► NAPQI (toxic reactive metabolite)
            ──Glutathione──► Non-toxic conjugate

2. Non-microsomal oxidation

Occurs in mitochondria, cytoplasm, plasma, and other tissues. It is mediated by enzymes such as:

Alcohol dehydrogenase
Aldehyde dehydrogenase
Monoamine oxidase
Xanthine oxidase

Enzyme	Example
Alcohol dehydrogenase	Ethanol → acetaldehyde
Aldehyde dehydrogenase	Acetaldehyde → acetate
Monoamine oxidase	Catecholamines, tyramine
Xanthine oxidase	6-mercaptopurine metabolism

B. Reduction

Reduction occurs in the microsomes and non-microsomal sites, especially when oxygen tension is low.

Types and examples

Reaction	Example
Azo reduction	Prontosil → sulfanilamide
Nitro reduction	Chloramphenicol; nitrazepam
Carbonyl reduction	Chloral hydrate → trichloroethanol
Disulfide reduction	Disulfiram metabolites
Reductive dehalogenation	Halothane metabolism

Exam line: Reduction is less common than oxidation but is important for drugs containing azo, nitro, and carbonyl groups.

C. Hydrolysis

Definition

Hydrolysis is cleavage of a drug molecule by addition of water, mediated by esterases, amidases, peptidases, and phosphatases.

Sites

Liver
Plasma
Intestinal mucosa
Kidney
Other tissues

Examples

Drug / compound	Hydrolytic product / enzyme
Procaine	Hydrolysed by plasma pseudocholinesterase
Succinylcholine	Hydrolysed by plasma pseudocholinesterase
Aspirin	Hydrolysed to salicylic acid
Atropine	Ester hydrolysis
Lidocaine	Amide hydrolysis, mainly hepatic
Enalapril	Hydrolysed to active enalaprilat
Heroin	Hydrolysed to morphine

Buzz words:
Ester drugs are rapidly hydrolysed by esterases, whereas amide-linked drugs are comparatively stable and mainly undergo hepatic metabolism.

II. Phase II Reactions: Conjugation / Synthetic Reactions

Definition

Phase II reactions involve covalent coupling of the drug or its Phase I metabolite with an endogenous, highly polar substrate.

Result

Drug / Phase I metabolite
          +
Endogenous conjugating moiety
          │
          ▼
Highly polar conjugate
          │
          ▼
Urinary or biliary excretion

Usually, conjugation causes inactivation and detoxification, but exceptions exist. Certain conjugation products can be reactive or toxic, including N-acetylation of isoniazid and some glucuronide conjugates. Katzung's Basic & Clinical Pharmacology, 16th ed., Chapter 4.

Major Phase II Reactions

Reaction	Donor / cofactor	Enzyme	Important examples
Glucuronidation	UDP-glucuronic acid	UDP-glucuronosyl transferase	Morphine, paracetamol, chloramphenicol, lorazepam
Sulfation	PAPS	Sulfotransferase	Paracetamol, methyldopa, steroid hormones
Acetylation	Acetyl-CoA	N-acetyltransferase	Isoniazid, hydralazine, procainamide, sulfonamides
Methylation	S-adenosyl methionine	Methyltransferase	Adrenaline, noradrenaline, histamine, 6-mercaptopurine
Glutathione conjugation	Glutathione	Glutathione-S-transferase	NAPQI from paracetamol
Amino acid conjugation	Glycine / glutamine etc.	Acyl transferase	Salicylic acid + glycine → salicyluric acid

A. Glucuronidation

Key facts

Most common Phase II reaction
Donor: UDP-glucuronic acid (UDPGA)
Enzyme: UDP-glucuronosyl transferase (UGT)
Mainly occurs in hepatic microsomes
Forms water-soluble glucuronides, excreted in urine or bile.

Examples

Morphine ──► Morphine glucuronide
Paracetamol ──► Paracetamol glucuronide
Chloramphenicol ──► Chloramphenicol glucuronide
Lorazepam ──► Lorazepam glucuronide

Clinical relevance:
Neonates have deficient glucuronidation. Chloramphenicol may accumulate and cause gray baby syndrome.

B. Acetylation

Key facts

Donor: Acetyl-CoA
Enzyme: N-acetyltransferase
Site: Mainly cytoplasm of liver
Includes genetic polymorphism, producing slow acetylators and fast acetylators.

Examples

Isoniazid
Hydralazine
Procainamide
Sulfonamides
Dapsone

Clinical importance of slow acetylators

Drug	Consequence in slow acetylator
Isoniazid	Peripheral neuropathy, hepatotoxicity
Hydralazine	Drug-induced lupus erythematosus
Procainamide	Lupus-like syndrome

Exam buzz words:
NAT2 polymorphism - fast acetylator - slow acetylator - pharmacogenetic variation.

C. Sulfation

Donor: PAPS: 3′-phosphoadenosine-5′-phosphosulfate
Enzyme: Sulfotransferase
Usually occurs in the cytosol.

Examples

Paracetamol
Methyldopa
Steroid hormones
Phenolic drugs

D. Methylation

Donor: S-adenosyl methionine (SAM)
Enzyme: Methyltransferase
In contrast to most conjugations, methylation may not markedly increase water solubility.

Examples

Noradrenaline / adrenaline ──COMT──► methylated metabolites
Histamine ──► methylhistamine
6-mercaptopurine ──TPMT──► methylated metabolite

Clinical point: TPMT deficiency can cause severe myelotoxicity with thiopurines.

E. Glutathione Conjugation

Endogenous substrate: Reduced glutathione (GSH)
Enzyme: Glutathione-S-transferase
Role: Detoxifies electrophilic reactive metabolites.

Classic example: Paracetamol

Paracetamol
   ├── Glucuronidation / sulfation ──► non-toxic metabolites
   │
   └── CYP2E1 ──► NAPQI (toxic electrophilic metabolite)
                      │
                      ├── GSH conjugation ──► non-toxic excretion
                      │
                      └── In overdose: GSH depleted
                                │
                                ▼
                         Hepatic necrosis

Antidote: N-acetylcysteine, which replenishes glutathione.

F. Amino Acid Conjugation

Examples:

Salicylic acid + glycine ──► Salicyluric acid
Benzoic acid + glycine ──► Hippuric acid

Microsomal Versus Non-microsomal Drug Metabolism

Feature	Microsomal metabolism	Non-microsomal metabolism
Location	Smooth ER, mainly liver	Cytoplasm, mitochondria, plasma, tissues
Major enzymes	CYP450, UGT	Esterases, amidases, MAO, alcohol dehydrogenase, NAT
Main reactions	Oxidation, some reduction, glucuronidation	Hydrolysis, acetylation, sulfation, methylation, oxidation
Drug induction	Present	Usually absent
Drug inhibition	Present	Usually absent/minimal
Genetic polymorphism	Important	Important for some enzymes, e.g., NAT2, TPMT
Examples	Warfarin, diazepam, phenytoin	Procaine, succinylcholine, isoniazid, ethanol

Final Exam Conclusion

Biotransformation is a protective metabolic process that converts lipid-soluble drugs into more polar metabolites for elimination. It occurs predominantly in the liver and comprises:

PHASE I = Oxidation + Reduction + Hydrolysis
PHASE II = Conjugation / Synthetic reactions

However, metabolism can also lead to:

Bioinactivation     → chloramphenicol
Bioactivation       → enalapril to enalaprilat
Active metabolite   → codeine to morphine
Toxic metabolite    → paracetamol to NAPQI

The two most examinable take-home lines are:

“Phase I reactions introduce or unmask a functional group, whereas Phase II reactions conjugate the drug with an endogenous polar moiety.”
“Drug metabolism usually detoxifies and facilitates excretion, but may also activate prodrugs or generate active and toxic metabolites.”

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