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Here is a thorough, textbook-based explanation of Biotransformation:

Biotransformation

Definition

Biotransformation is the chemical modification of a drug (or other xenobiotic) within the body - primarily by the liver - that converts it into a different chemical form, usually more polar (water-soluble), so it can be excreted. It is the metabolic phase of pharmacokinetics (Absorption → Distribution → Biotransformation → Excretion).

"Biotransformation includes the chemical processes by which the drug molecule is altered in the body."

Morgan and Mikhail's Clinical Anesthesiology, 7e

Sites of Biotransformation

Site	Significance
Liver	Primary organ; contains microsomal enzymes (CYP450, UGT, GST, sulfotransferases)
Gastrointestinal tract	Intestinal wall contributes significantly (e.g., midazolam ~50% intestinal)
Lungs, Skin, Kidneys, Brain	Minor roles
Plasma/Tissues	Ester hydrolysis (e.g., ester-type local anesthetics like succinylcholine)

After oral administration, many drugs (isoproterenol, morphine, lidocaine) undergo extensive first-pass hepatic metabolism before reaching systemic circulation. - Katzung's Basic & Clinical Pharmacology, 16e

The Two Phases of Biotransformation

The biotransformation of drugs - Phase I and Phase II

Phase I Reactions - "Functionalization"

Goal: Convert lipophilic parent drug into more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH).

Reactions:

Oxidation (most common)
Reduction
Hydrolysis

Key enzyme system: Cytochrome P450 (CYP) - located in the smooth endoplasmic reticulum of hepatocytes. Requires NADPH and O2.

Effect on activity:

Most often → inactivation of the drug
Sometimes → activation (prodrugs, e.g., codeine → morphine)
Sometimes → toxic metabolites (e.g., acetaminophen overdose → NAPQI via CYP2E1)

Non-CYP Phase I reactions:

Amine oxidation (catecholamines, histamine)
Alcohol dehydrogenation (ethanol)
Esterase hydrolysis (aspirin)

Phase II Reactions - "Conjugation / Synthetic"

Goal: Couple a Phase I metabolite (or sometimes the parent drug directly) with an endogenous polar molecule to form a highly water-soluble conjugate excreted in urine or bile.

Conjugation substrates:

Reaction	Endogenous Substrate	Key Enzyme	Examples
Glucuronidation	UDP-glucuronic acid	UDP-glucuronyl transferase (UGT)	Bilirubin, morphine, acetaminophen
Sulfation	PAPS (3'-phosphoadenosine-5'-phosphosulfate)	Sulfotransferase	Thyroxine, bile acids, acetaminophen
Acetylation	Acetyl-CoA	N-acetyltransferase (NAT)	Isoniazid, sulfonamides
Glutathione conjugation	Glutathione (GSH)	GSH S-transferase	Electrophilic metabolites (e.g., NAPQI)
Amino acid conjugation	Glycine, glutamine	-	Aspirin metabolites

Result: Phase II products are usually pharmacologically inactive and excreted. A notable exception is morphine-6-glucuronide, which is more potent than morphine itself.

"Glucuronidation is the most common and the most important conjugation reaction." - Lippincott Pharmacology

Important Nuance: Phase II Before Phase I

The traditional sequence (Phase I → Phase II) is not absolute. For example:

Isoniazid (INH): The hydrazide moiety first undergoes Phase II acetylation to form N-acetyl-INH, which then undergoes Phase I hydrolysis to isonicotinic acid. Phase II actually comes first here.
Drugs with existing -OH, -NH2, or -COOH groups can bypass Phase I and go directly to Phase II conjugation.

Cytochrome P450 (CYP) System - Key Isoforms

CYP isoform contribution to drug biotransformation

Isoform	% Contribution	Key Substrates	Key Inducers	Key Inhibitors
CYP3A4/5	36% (largest)	Carbamazepine, cyclosporine, erythromycin, nifedipine, simvastatin	Rifampin, phenobarbital, phenytoin, carbamazepine	Ketoconazole, ritonavir, clarithromycin
CYP2D6	19%	Fluoxetine, haloperidol, paroxetine, propranolol	None significant	Fluoxetine, paroxetine
CYP2C8/9	16%	Warfarin, NSAIDs	Rifampin	Omeprazole
CYP1A2	11%	Theophylline, caffeine	Tobacco smoke, omeprazole	Fluvoxamine
CYP2C19	8%	PPIs, diazepam, clopidogrel	Rifampin	Omeprazole
CYP2E1	4%	Ethanol, acetaminophen	Ethanol, isoniazid	Disulfiram

Hepatic Clearance Concepts

Extraction Ratio (ER) = fraction of drug removed by the liver in a single pass.

Type	Extraction Ratio	Clearance depends on	Examples	Effect of enzyme induction
High ER (flow-dependent)	>0.7	Liver blood flow	Propofol, lidocaine, morphine, nitroglycerin, propranolol	Minimal effect
Low ER (capacity-dependent)	<0.3	Enzyme capacity	Methadone (10%), alfentanil (15%), warfarin	Significant increase in clearance

Enzyme Induction and Inhibition

Induction = increased synthesis of CYP enzymes → faster drug metabolism → lower plasma levels → potential treatment failure.

Classic inducers: Phenobarbital (broad, increases P450 reductase), rifampin, carbamazepine, tobacco smoke (induces CYP1A2)

Inhibition = competition or blocking of CYP → slower metabolism → drug accumulation → toxicity.

Classic inhibitors: Ketoconazole, ritonavir, clarithromycin (inhibit multiple CYPs), omeprazole (warfarin interaction)
Mechanisms: substrate competition, competitive inhibition, non-competitive inhibition, product inhibition

Factors Affecting Biotransformation Rate

Age: Neonates and elderly have reduced CYP activity
Genetics: Polymorphisms in CYP2D6, CYP2C19 → poor vs. extensive metabolizers
Disease: Cirrhosis, hepatitis → reduced metabolic capacity
Gender: Minor differences in CYP activity
Drug-drug interactions: Induction/inhibition of shared CYP isoforms
Diet: Grapefruit juice inhibits CYP3A4 in the gut wall

Biotransformation and Toxicity

Some drugs generate toxic reactive intermediates during Phase I metabolism:

Acetaminophen: CYP2E1/CYP3A4 generates NAPQI (N-acetyl-p-benzoquinone imine) - normally detoxified by GSH. In overdose, GSH is depleted → hepatic necrosis.
Isoniazid: CYP450 bioactivation → isonicotinic acyl radical → binds hepatic proteins → idiosyncratic immunotoxicity.
Halothane, phenothiazines: Converted to reactive forms → cellular injury.
Carcinogens: CYP450 enzymes activate aromatic carcinogens to their active mutagenic forms.

Sources:

Morgan and Mikhail's Clinical Anesthesiology, 7e, pp. 265-266
Lippincott Illustrated Reviews: Pharmacology, pp. 55-61
Katzung's Basic and Clinical Pharmacology, 16e, pp. 93-95
Mulholland and Greenfield's Surgery, 7e, pp. 92-94
Tietz Textbook of Laboratory Medicine, 7e

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+8 more

Make revesion flashcards of these topics from my book and mcqs for practise i will see Tommrow before starting micro and patho

analyse_media

Good luck tomorrow! Here are all your revision flashcards + MCQs based directly on your book pages:

📚 PHARMACOKINETICS - REVISION FLASHCARDS

TOPIC 1: BIOAVAILABILITY

CARD 1 Q: What is the FDA definition of bioavailability? A: The rate at which AND the extent to which the active concentration of the drug is available at the desired site of action. Measured by AUC (area under concentration-time curve).

CARD 2 Q: What is the bioavailability via IV route? Why? A: 100% - because drug is directly administered into systemic circulation.

CARD 3 Q: Why is oral bioavailability < 100%? (2 main reasons) A:

Incomplete absorption - drug not fully absorbed from GIT
First-pass metabolism - drug metabolised in gut wall + liver before reaching systemic circulation

CARD 4 Q: Atenolol is too ________ → fails to cross lipid cell membrane. Acyclovir is too ________ → can't cross water layer. A: Atenolol = too hydrophilic. Acyclovir = too lipophilic.

CARD 5 Q: What is the formula for Extraction Ratio (ER)? A: ER = CL(liver) / Q

CL(liver) = drug clearance by liver
Q = hepatic blood flow (normally 90 L/hour in 70 kg adult)

CARD 6 Q: What is the formula for systemic bioavailability (F)? A: F = f × (1 - ER) Full form: F = f × (1 - CL(liver)/Q)

f = fraction absorbed
ER = extraction ratio

TOPIC 2: FACTORS AFFECTING BIOAVAILABILITY

CARD 7 Q: Order of bioavailability by formulation type (highest to lowest)? A: Solution > Suspension > Tablet > Coated tablet > Capsule

CARD 8 Q: How does particle size affect bioavailability? A: Smaller (microfine) particles = higher bioavailability due to better dissolution. Example: sodium tolbutamide > tolbutamide.

CARD 9 Q: Amorphous vs crystalline form - which has higher bioavailability? A: Amorphous form has higher bioavailability (dissolves faster). Example: amorphous chloramphenicol palmitate > crystalline form.

CARD 10 Q: Which highly polar drugs are NOT absorbed orally (low bioavailability)? A: Streptomycin, acetylcholine, neostigmine (too ionised/polar to be absorbed).

CARD 11 Q: How do chlorpromazine and propranolol affect each other's bioavailability when given together? A: They compete for the same hepatic metabolising enzymes → reduced first-pass metabolism of each other → increased oral bioavailability of both.

CARD 12 Q: Effect of severe hepatic disease on oral bioavailability? A: Decreases first-pass metabolism → increased oral bioavailability → risk of toxicity with usual doses.

CARD 13 Q: What is bioequivalence vs chemical equivalence? A: Chemical equivalence = same amount of drug. Bioequivalence = same blood levels/pharmacological effect. Two formulations can be chemically equivalent but biologically inequivalent (e.g., different digoxin formulations).

CARD 14 Q: Classic example of bioinequivalence? A: Phenytoin ('Dilantin sodium') in Australia 1968 - calcium sulphate replaced by lactose as diluent → lactose dissolved faster → toxic plasma levels of phenytoin.

TOPIC 3: VOLUME OF DISTRIBUTION (aVd)

CARD 15 Q: Define apparent Volume of Distribution (aVd). A: The theoretical volume the body would need to have if the drug concentration throughout was the same as in plasma. Formula: aVd = Total drug in body (Q) / Plasma concentration (Cp)

CARD 16 Q: Why is it called "apparent" Vd? A: Because the body is not a single homogeneous compartment. It's a theoretical/calculated value.

CARD 17 Q: Drugs with HIGH plasma protein binding have ____ aVd. Example? A: LOW aVd (drug stays in vascular compartment). Example: Warfarin - 90% protein bound → aVd = 0.15 L/kg (≈ plasma volume).

CARD 18 Q: What are the consequences of HIGH plasma protein binding (PPB)? (4 points) A:

Low aVd (drug retained in vascular compartment)
Acts as temporary storage → increases duration of action
Dialysis has NO role in toxicity (can't filter protein-bound drug)
Risk of displacement reactions when two highly bound drugs compete for same binding site

CARD 19 Q: Acidic drugs bind to ______. Basic drugs bind to ______. A:

Acidic drugs → Albumin (e.g., barbiturates, benzodiazepines, phenytoin, valproate, NSAIDs, penicillins, sulphonamides, tetracyclines)
Basic drugs → α1-acid glycoprotein (e.g., verapamil, lignocaine, bupivacaine, quinidine, disopyramide, beta blockers)

CARD 20 Q: What 3 factors determine fraction of drug bound to plasma protein? A:

Number of binding sites
Affinity of drug for plasma proteins
Drug concentration

TOPIC 4: DRUG METABOLISM / BIOTRANSFORMATION

CARD 21 Q: Define biotransformation. A: The process of converting lipid-soluble, non-polar (unionised) drugs into lipid-insoluble, ionised forms in the body to make them excretable by the kidney.

CARD 22 Q: Principal organ of drug metabolism? Other sites? A: Liver is principal. Others: intestines (lumen + wall), lungs, skin, kidneys.

CARD 23 Q: What is first-pass metabolism / pre-systemic metabolism? A: Metabolism that occurs when the drug passes through the gut wall + portal blood + liver for the first time, before reaching systemic circulation. Results in reduced bioavailability.

CARD 24 Q: Name drugs with VERY HIGH first-pass metabolism (not used orally)? A: Testosterone, Morphine, Isoprenaline, Lignocaine, Hydrocortisone Mnemonic: "The Man Is Lying Here"

CARD 25 Q: Name drugs with HIGH first-pass metabolism (low oral bioavailability)? A: Propranolol, Alprenolol, Verapamil, Salbutamol, Nitroglycerine, Methyltestosterone, Pethidine

CARD 26 Q: What is Phase I reaction? What functional groups are introduced/unmasked? A: Non-synthetic reactions. Introduce or unmask -OH, -SH, or -NH2 groups. Types: Oxidation, Reduction, Hydrolysis. Makes drug more polar/excretable. Metabolites may be inactive, active, or toxic.

CARD 27 Q: What is Phase II reaction? A: Synthetic (conjugation) reactions. Couple a drug or Phase I metabolite with an endogenous substrate (glucuronide, sulphate, glycine, acetate, methyl) to form water-soluble conjugate for excretion. Metabolites usually inactive (exception: morphine-6-glucuronide is more potent than morphine).

CARD 28 Q: Phase II reactions are usually _____ than Phase I. Metabolites are mostly _____. A: Faster than Phase I. Metabolites mostly inactive.

CARD 29 Q: Can Phase II precede Phase I? Give example. A: YES. Isoniazid (INH): first acetylated (Phase II) → then hydrolysed (Phase I) to isonicotinic acid.

CARD 30 Q: Phase I drugs - CYP450 dependent oxidation examples (circle-marked in your book)? A: Phenobarbital, Phenytoin, Carbamazepine, Morphine, Codeine, Propranolol, Acetaminophen, Diazepam

CARD 31 Q: Phase I reduction examples? A: Chloramphenicol, clonazepam, dantrolene, methadone, naloxone

CARD 32 Q: Phase I hydrolysis examples? A: Procaine, lignocaine, procainamide, aspirin, indomethacin, succinylcholine

CARD 33 Q: Phase II - Acetylation examples? A: Isoniazid, sulphonamides, dapsone, hydralazine, procainamide

CARD 34 Q: Phase II - Methylation examples? A: Adrenaline, Dopamine, Histamine

CARD 35 Q: Phase II - Glucuronide conjugation examples? A: Diazepam, Digoxin, Digitoxin, morphine, meprobamate

CARD 36 Q: Phase II - Sulfation examples? A: Methyldopa, acetaminophen

CARD 37 Q: Phase II - Glutathione conjugation examples? A: Acetaminophen, ethacrynic acid

TOPIC 5: DRUG-METABOLISING ENZYMES

CARD 38 Q: Where are microsomal enzymes located? What are the most important ones? A: In the endoplasmic reticulum of the liver and other tissues. Most important: Mixed-Function Oxidases (MFOs) / Monooxygenases. Two key enzymes: Flavoprotein (NADPH-CYP450 reductase) + Hemoprotein (Cytochrome P450).

CARD 39 Q: Which CYP isoform metabolises >50% of prescription drugs? A: CYP3A4 (accounts for ~36% of drug biotransformation)

CARD 40 Q: Enzyme induction: What is the main mechanism? How long does it take? A: Increased synthesis of enzyme protein (mainly cytochrome P450 + glucuronyl transferase). Takes 4-14 days to reach peak. Levels return to normal 1-3 weeks after stopping inducer.

CARD 41 Q: Which CYP is induced by tobacco smoke + cruciferous vegetables? A: CYP1A2 (also induced by omeprazole)

CARD 42 Q: Which CYP is induced by ethanol and isoniazid? A: CYP2E1

CARD 43 Q: Which CYPs are induced by barbiturates and rifampicin? A: CYP2A6, 2B6, 2C8, 2C9, and 2C19

CARD 44 Q: Which CYP is induced by rifampicin, phenobarbitone, phenytoin, carbamazepine, atorvastatin? A: CYP3A4

CARD 45 Q: What is autoinduction? Example? A: When an inducing drug increases its own metabolism. Examples: Rifampicin and carbamazepine can induce their own metabolism.

CARD 46 Q: Clinical implications of enzyme induction (5 points)? A:

Increased inactivation of simultaneously given drugs (e.g., rifampicin → contraceptive failure)
Autoinduction (rifampicin, carbamazepine)
Increased metabolism of endogenous substances (steroids, bilirubin)
Phenytoin useful in Cushing's syndrome (increases cortisol metabolism)
Phenobarbitone: clears congenital haemolytic jaundice; porphyrin synthesis increased by barbiturates (precipitates acute intermittent porphyria)
Prodrugs are activated by enzyme induction

CARD 47 Q: What are suicide inhibitors of CYP? Examples? A: Drugs that bind irreversibly to CYP450 apoprotein or heme by covalent bonding → permanent inhibition. Examples: Grapefruit juice, clopidogrel, ritonavir, propylthiouracil, ticlopidine.

CARD 48 Q: What is slow vs fast acetylator? Clinical significance? A:

Fast acetylators: Drug inactivated quickly → may need higher dose; reduced efficacy
Slow acetylators: Drug inactivated slowly → risk of adverse effects
- Isoniazid → peripheral neuropathy in slow acetylators
- Hydralazine + procainamide → risk of lupus in slow acetylators

🎯 MCQ PRACTICE (30 Questions)

Q1. A 70 kg adult has a hepatic blood flow of 90 L/hour. A drug has hepatic clearance of 45 L/hour. What is its extraction ratio?

A) 25%
B) 50% ✅
C) 75%
D) 90%

ER = CL(liver)/Q = 45/90 = 0.5 = 50%

Q2. Which of the following has 100% oral bioavailability?

A) Morphine
B) Lignocaine
C) Intravenous glucose ✅
D) Propranolol

IV route = always 100% bioavailability

Q3. Atenolol has low oral bioavailability because it is:

A) Too lipophilic
B) Too hydrophilic ✅
C) Highly protein bound
D) A prodrug

Too hydrophilic → cannot cross lipid cell membrane

Q4. The bioavailability of different formulations in correct descending order is:

A) Tablet > Suspension > Solution > Capsule
B) Solution > Suspension > Tablet > Coated tablet > Capsule ✅
C) Capsule > Coated tablet > Tablet > Suspension > Solution
D) Solution > Tablet > Suspension > Capsule > Coated tablet

Q5. Amorphous chloramphenicol palmitate has better bioavailability than crystalline form because:

A) It is more lipophilic
B) It has smaller particle size
C) It dissolves faster ✅
D) It has lower plasma protein binding

Q6. Which drug is NOT used orally due to very high first-pass metabolism?

A) Warfarin
B) Phenytoin
C) Morphine ✅
D) Digoxin

Q7. First-pass metabolism involves metabolism in: (Select all correct)

A) Gut wall ✅
B) Portal blood ✅
C) Liver ✅
D) Kidney

All three - gut wall, portal blood, AND liver

Q8. Warfarin has aVd of 0.15 L/kg. This means:

A) It is highly lipid soluble
B) It is widely distributed to tissues
C) It is highly plasma protein bound ✅
D) It undergoes first-pass metabolism

Q9. Dialysis is NOT useful in toxicity of which drug?

A) Lithium
B) Warfarin ✅
C) Phenobarbitone
D) Salicylates

Warfarin is 90% protein bound → dialysis cannot filter it

Q10. Acidic drugs bind to:

A) α1-acid glycoprotein
B) Albumin ✅
C) β-globulin
D) γ-globulin

Acidic → albumin. Basic → α1-acid glycoprotein

Q11. Which of the following is a Phase I reaction?

A) Glucuronidation
B) Acetylation
C) Sulfation
D) Hydrolysis ✅

Q12. Phase II reactions are called synthetic because:

A) They introduce functional groups
B) They conjugate drug with endogenous substrate ✅
C) They require NADPH
D) They occur in ER

Q13. Morphine-6-glucuronide is notable because:

A) It is less potent than morphine
B) It is more potent than morphine ✅
C) It is a Phase I metabolite
D) It is formed by sulfation

Q14. Isoniazid is first ____ (Phase II), then ____ (Phase I):

A) Hydroxylated, then conjugated
B) Acetylated, then hydrolysed ✅
C) Hydrolysed, then acetylated
D) Glucuronidated, then oxidised

Q15. Chloramphenicol is metabolised by which Phase I reaction?

A) Oxidation
B) Hydrolysis
C) Reduction ✅
D) Acetylation

Q16. Procaine is metabolised by which Phase I reaction?

A) Oxidation
B) Reduction
C) Hydrolysis ✅
D) Methylation

Q17. Which drugs undergo methylation (Phase II)?

A) Isoniazid, sulphonamides
B) Adrenaline, dopamine, histamine ✅
C) Diazepam, digoxin
D) Acetaminophen, ethacrynic acid

Q18. Microsomal enzymes are located in:

A) Mitochondria
B) Cytoplasm
C) Endoplasmic reticulum ✅
D) Golgi apparatus

Q19. CYP3A4 metabolises approximately what percentage of prescription drugs?

A) 11%
B) 19%
C) 36% ✅ (over 50% of prescription drugs per your book text)
D) 50%

Q20. Enzyme induction takes how long to reach peak effect?

A) 1-2 days
B) 4-14 days ✅
C) 2-3 weeks
D) 1-2 months

Q21. Rifampicin causes contraceptive failure due to:

A) Inhibiting CYP3A4
B) Inducing CYP3A4 → increases metabolism of oral contraceptives ✅
C) Displacing contraceptive from protein binding
D) Reducing GI absorption

Q22. Which drug can precipitate acute intermittent porphyria by inducing delta-ALA synthase?

A) Rifampicin
B) Barbiturates ✅
C) Carbamazepine
D) Phenytoin

Q23. CYP1A2 is induced by:

A) Rifampicin
B) Ethanol
C) Tobacco smoke ✅
D) Barbiturates

Q24. CYP2E1 is induced by:

A) Tobacco smoke
B) Ethanol + Isoniazid ✅
C) Rifampicin
D) Omeprazole

Q25. Which is an example of autoinduction?

A) Rifampicin causing contraceptive failure
B) Carbamazepine increasing its own metabolism ✅
C) Phenytoin treating Cushing's syndrome
D) Phenobarbitone clearing jaundice

Q26. Slow acetylators are at risk of (isoniazid):

A) Hepatotoxicity (fast acetylators risk this more)
B) Peripheral neuropathy ✅
C) Optic neuritis
D) Drug resistance

Q27. Which of the following is a suicide inhibitor of CYP?

A) Rifampicin
B) Phenobarbitone
C) Grapefruit juice ✅
D) Carbamazepine

Q28. Phenytoin may be useful in Cushing's syndrome because:

A) It inhibits cortisol synthesis
B) It induces CYP enzymes → increases cortisol metabolism ✅
C) It blocks cortisol receptors
D) It increases ACTH

Q29. A patient on severe hepatic disease takes propranolol. What happens?

A) Decreased bioavailability due to poor absorption
B) Increased bioavailability due to reduced first-pass metabolism ✅
C) No change in bioavailability
D) Increased first-pass metabolism

Q30. Which of the following undergoes glucuronide conjugation (Phase II)?

A) Isoniazid
B) Adrenaline
C) Digoxin ✅
D) Methyldopa

Quick Summary Table (Stick on your desk tonight)

Topic	Key Point
Bioavailability	AUC; IV=100%; F = f×(1-ER)
First-pass	Gut wall + Portal blood + Liver
Very high FPM (not oral)	Testosterone, Morphine, Isoprenaline, Lignocaine, Hydrocortisone
Formulation order	Solution > Suspension > Tab > Coated tab > Capsule
Warfarin	90% PPB, aVd = 0.15 L/kg, no dialysis
Acidic drugs	Bind albumin
Basic drugs	Bind α1-acid glycoprotein
Phase I	Non-synthetic; -OH/-SH/-NH2; Oxidation/Reduction/Hydrolysis
Phase II	Synthetic/Conjugation; mostly inactive products
CYP3A4	Biggest isoform (36%); induced by rifampicin
CYP1A2	Induced by tobacco smoke
CYP2E1	Induced by ethanol + isoniazid
Enzyme induction	Peaks in 4-14 days
Slow acetylators	INH → neuropathy; Hydralazine → lupus
Isoniazid metabolism	Phase II (acetylation) FIRST, then Phase I (hydrolysis)

Good luck tomorrow! Cover these 30 MCQs first, then scan the quick summary table right before you start micro and patho. 💪

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