💊 ADME in Pharmacology: The Journey of a Drug Through the Body

Every medication you take goes on a complex journey through your body. This journey—known as ADME—determines whether a drug works, how long it stays active, and how it’s cleared from the system.

ADME stands for:

• • Absorption
• • Distribution
• • Metabolism
• • Excretion

Understanding these processes is crucial for designing effective drugs and ensuring safe, personalized therapies. In this article, we’ll explore each phase of the ADME journey in detail, supported by real-life examples and applications in pharmacy.

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🚪 1. Absorption: Entry Into the Body

📌 What Is Absorption?

Absorption refers to the process by which a drug moves from its site of administration into the bloodstream.

🚩 Factors Influencing Absorption

A. Route of Administration

• • Oral (PO): Most common. Absorbed through GI tract.
• • Intravenous (IV): Directly enters circulation—100% bioavailability.
• • Intramuscular (IM) & Subcutaneous (SC): Slower onset.
• • Sublingual: Rapid absorption through mucosa.
• • Rectal, Inhalation, Topical: Site-specific absorption patterns.

B. Physicochemical Properties

• • Solubility: Drugs must dissolve to be absorbed.
• • Lipophilicity: Lipid-soluble drugs pass through cell membranes more easily.
• • Molecular Size: Smaller molecules absorb faster.

C. Formulation Factors

Tablet coatings, excipients, extended-release technologies all affect absorption rate.

D. Biological Factors

• • Gastric pH: Some drugs degrade in acidic stomach (e.g., penicillin G).
• • Food presence: May enhance (griseofulvin) or hinder (tetracycline) absorption.
• • GI motility: Faster emptying = quicker absorption.

🧪 Special Case: First-Pass Metabolism

Drugs absorbed through the GI tract enter the hepatic portal vein and pass through the liver before reaching systemic circulation. Some are extensively metabolized and inactivated here (e.g., propranolol).

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🧪 2. Distribution: Spreading Through the Body

📌 What Is Distribution?

Once absorbed, drugs are distributed via the bloodstream to tissues and organs. Distribution describes how and where a drug spreads within the body.

🔍 Key Concepts

A. Volume of Distribution (Vd)

A theoretical volume indicating how extensively a drug disperses beyond the plasma.

• - Low Vd: Drug stays in blood (e.g., heparin).
• - High Vd: Drug enters fat, muscle, or other tissues (e.g., chloroquine).

B. Plasma Protein Binding

• - Drugs can bind to albumin (acidic drugs) or alpha-1 acid glycoprotein (basic drugs).
• - Only the free (unbound) drug is pharmacologically active.
• - High binding reduces availability and delays clearance.

C. Tissue Binding

Some drugs accumulate in specific tissues:

• - Tetracycline: Bones and teeth
• - Amiodarone: Fat tissue
• - Iodine: Thyroid gland

D. Blood-Brain Barrier (BBB)

The BBB limits access to the CNS. Only lipid-soluble, low-molecular-weight drugs can pass easily (e.g., diazepam). Polar or large molecules (e.g., dopamine) require transporters or prodrug strategies.

📦 Special Distribution Examples

• - Pregnancy: Drugs can cross the placenta and affect the fetus.
• - Breast Milk: Lipid-soluble drugs may be excreted in breast milk.

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🔥 3. Metabolism: Chemical Modification

📌 What Is Metabolism?

Metabolism transforms drugs into more water-soluble compounds, aiding in their excretion. This usually occurs in the liver, though other organs contribute.

♻ Types of Metabolic Reactions

• Phase I: Functionalization

• - Introduces or uncovers a polar group (OH, NH₂).
• - Involves oxidation, reduction, hydrolysis.
• - Major enzymes: Cytochrome P450 (CYP450) family.

Examples:

• - Codeine → morphine (via CYP2D6)
• - Diazepam → nordiazepam (via CYP3A4)

• Phase II: Conjugation

• - Adds large polar molecules to increase water solubility.
• - Common conjugates: glucuronic acid, sulfate, glutathione.

Examples:

• - Paracetamol → glucuronide or sulfate conjugate
• - Morphine → morphine-6-glucuronide (active)

🧬 Genetic Variability in Metabolism

Pharmacogenetics:

• • Slow acetylators: Higher risk of isoniazid toxicity.
• • CYP2C19 variants: Affect clopidogrel activation.
• • CYP2D6 polymorphism: Alters response to antidepressants, opioids.

♻ First-Pass Effect Revisited

Drugs like propranolol and nitroglycerin are significantly metabolized before reaching systemic circulation, reducing their oral bioavailability.

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🚽 4. Excretion: Leaving the Body

📌 What Is Excretion?

Excretion is the process by which drugs and their metabolites are eliminated from the body. The kidneys are the primary route, but other organs also play a role.

🏃 Routes of Excretion

A. Renal Excretion

• Three steps:

• - Glomerular filtration: Only free drug is filtered.
• - Tubular secretion: Active transport of drugs into urine.
• - Reabsorption: Lipid-soluble drugs may be reabsorbed into blood.

• Factors:

• - pH of urine (ion trapping)
• - Renal function (elderly, kidney disease)

• Examples:

• - Aminoglycosides, digoxin: primarily renal
• - Adjust doses in renal impairment

B. Biliary and Fecal Excretion

• Larger or conjugated molecules (e.g., glucuronides) secreted into bile.
• May undergo enterohepatic recycling—reabsorbed from the intestine, prolonging action (e.g., oral contraceptives).

C. Pulmonary Excretion

Volatile anesthetics (e.g., isoflurane) exhaled through lungs.

D. Other Routes

Sweat, saliva, tears, and breast milk (may pose risk to nursing infants).

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📉 Pharmacokinetic Parameters Derived from ADME

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📊 Case Study: ADME of Paracetamol (Acetaminophen)

• • Absorption: Rapid oral absorption, peak in 30–60 mins
• • Distribution: Widely distributed, crosses placenta
• • Metabolism:
• - Phase II: Glucuronidation & sulfation (major)
• - Phase I: Small portion → toxic metabolite (NAPQI)
• - Detoxified by glutathione
• • Excretion: Renal, mostly as conjugated metabolites
• • Overdose leads to glutathione depletion → hepatotoxicity.

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🌍 Real-World Applications of ADME

1. • Drug Design and Development
   • - Lipinski’s Rule of Five: Predicts good oral bioavailability based on absorption traits.
   • - Early ADME profiling avoids late-stage drug failures.
2. • Personalized Medicine
   • - Pharmacogenomics tailors dosing based on metabolism rate.
   • - ADME data helps determine drug safety in special populations (children, elderly, pregnancy).
3. • Drug Interactions
   • - Enzyme inducers (e.g., rifampicin) ↑ metabolism = ↓ drug effect
   • - Enzyme inhibitors (e.g., ketoconazole) ↓ metabolism = ↑ toxicity risk
4. • Dose Adjustment
   • - In liver or kidney disease, ADME changes demand dose modifications.
   • - Therapeutic Drug Monitoring (TDM) relies on ADME to maintain drug levels (e.g., vancomycin, phenytoin).

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🔬 Advanced Tools in ADME Research

• • In vitro models: Caco-2 cells for absorption studies.
• • Microdosing: Uses trace doses to study pharmacokinetics.
• • Physiologically-Based Pharmacokinetic (PBPK) Modeling: Simulates ADME in silico.

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🧠 Final Thoughts

The ADME processes determine the fate of a drug—from how it's taken up by the body to how it’s cleared. A drug might be potent in the lab, but without favorable ADME properties, it won’t be effective or safe in real patients.

For healthcare professionals, understanding ADME helps:

• • Choose the right drug and route
• • Avoid toxicity and interactions
• • Personalize therapy for better outcomes

Whether you’re a pharmacy student or a practicing clinician, ADME is at the heart of rational pharmacotherapy.