Introduction to Biopharmaceutics – Absorption & Distribution
This foundational unit introduces biopharmaceutics and covers two critical ADME processes: (1) Absorption — mechanisms of drug transport across biological membranes (passive diffusion, active transport, facilitated diffusion, pinocytosis), pH-partition theory, factors influencing GI absorption (physicochemical, physiological, dosage form), and absorption from non-oral routes. (2) Distribution — how drugs spread through body compartments, tissue permeability, apparent volume of distribution (Vd), plasma and tissue protein binding (kinetics, clinical significance).
Syllabus & Topics
- 1Introduction to Biopharmaceutics: Biopharmaceutics = study of the influence of physicochemical properties of the drug, dosage form design, and route of administration on the rate and extent of drug absorption. It bridges pharmaceutical sciences (formulation) and pharmacology (drug action). The biopharmaceutic classification system (BCS) categorizes drugs based on solubility and permeability. Key concept: same drug in different formulations can give very different blood levels → therapeutic inequivalence. This is why bioavailability and bioequivalence studies are necessary.
- 2Mechanisms of Drug Absorption – Passive Diffusion: Most common mechanism. Drug moves from HIGH concentration to LOW concentration across lipid membrane. Follows Fick’s First Law: dQ/dt = D·A·K·(Cgi − Cp) / h. Where: D = diffusion coefficient, A = surface area, K = partition coefficient, h = membrane thickness, (Cgi − Cp) = concentration gradient. Characteristics: no energy required, no carrier, not saturable, no competition, follows first-order kinetics. Lipophilic (unionized) drugs cross membranes better. pH-Partition Hypothesis: unionized form of drug crosses membrane → absorption depends on drug pKa and GI pH.
- 3pH-Partition Theory: Weak acids (HA → H⁺ + A⁻): unionized (HA) form predominates at pH < pKa → weak acids better absorbed from stomach (pH 1-3). Henderson-Hasselbalch: pH = pKa + log([A⁻]/[HA]). Example: Aspirin (pKa 3.5) → at stomach pH 1.5: ratio HA:A⁻ = 100:1 → mostly unionized → favors absorption. Weak bases (BH⁺ → B + H⁺): unionized (B) form predominates at pH > pKa → better absorbed from intestine (pH 5-8). Limitations: despite favorable pH in stomach, most drugs are better absorbed from intestine due to MUCH LARGER surface area (200 m² vs 1 m²) and longer transit time.
- 4Active Transport & Other Mechanisms: Active transport: carrier-mediated, against concentration gradient, requires energy (ATP), saturable, competitive, structure-specific. Examples: amino acids (L-DOPA), monosaccharides, vitamins (B₁, B₂, B₁₂), ions (Fe²⁺, Ca²⁺). Facilitated diffusion: carrier-mediated but DOWN concentration gradient → no energy needed → saturable, competitive. Examples: Vitamin B₁₂ (intrinsic factor-mediated), glucose (GLUT transporters). Pinocytosis/Endocytosis: cell membrane engulfs drug particle → forms vesicle → transports across. For large molecules (proteins, peptides). Ion-pair formation: charged drug + counter ion → neutral complex → crosses membrane by passive diffusion.
- 5Factors Influencing GI Absorption – Physicochemical: (1) Drug solubility: must dissolve before absorption (Noyes-Whitney equation). BCS Class II drugs → dissolution rate-limited. (2) Particle size: ↓size → ↑surface area → ↑dissolution → ↑absorption (Griseofulvin micronized). (3) Salt form: Na/K salts of weak acids dissolve faster; HCl salts of weak bases dissolve faster. (4) Crystal form: amorphous > crystalline (higher energy state). Polymorphism: different crystal forms → different solubility → different bioavailability (Chloramphenicol palmitate — polymorphs A, B, C). (5) pKa and lipophilicity (log P): optimal log P for oral absorption 1-3.
- 6Factors Influencing GI Absorption – Physiological: (1) GI pH: stomach (1-3), duodenum (5-6), jejunum/ileum (6-8) → affects ionization. (2) Gastric emptying rate: faster emptying → drug reaches absorptive intestine sooner. ↑by: metoclopramide, fasting, lying on right side. ↓by: fatty food, anticholinergics, lying on left side. (3) Intestinal motility: ↑motility → ↓contact time → ↓absorption (diarrhea). (4) Blood flow: mesenteric blood flow maintains sink conditions (concentration gradient). (5) GI surface area: enormous (villi + microvilli = 200 m²). (6) Food effects: can ↑ or ↓ absorption (Griseofulvin ↑ with fatty food; Tetracycline ↓ with dairy). (7) First-pass effect: drug absorbed from GI → portal vein → liver metabolism BEFORE reaching systemic circulation → ↓bioavailability.
- 7Factors – Dosage Form: (1) Disintegration: tablet must disintegrate into granules → granules into fine particles. (2) Dissolution: drug dissolves from particles (rate-limiting step for many drugs). (3) Excipients: binders (↓dissolution), disintegrants (↑dissolution), surfactants (↑wetting → ↑dissolution). (4) Coating: enteric coating delays dissolution to intestine; modified-release coatings control rate. (5) Dosage form type: solutions > suspensions > capsules > tablets > coated tablets (generally). BCS Classification: Class I (high solubility, high permeability — no issues), Class II (low solubility, high permeability — dissolution limited), Class III (high solubility, low permeability — permeability limited), Class IV (low solubility, low permeability — problematic).
- 8Absorption from Non-Peroral Routes: Sublingual/Buccal: venous drainage bypasses liver → NO first-pass effect. Thin mucosa, good blood supply. Examples: Nitroglycerin (sublingual), Fentanyl (buccal). Rectal: 50% bypasses first-pass (lower rectal veins drain into inferior vena cava, not portal vein). For nauseous/unconscious patients. Pulmonary: rapid absorption (thin alveolar membrane, large surface area ~100 m², high blood flow). Examples: inhaled anesthetics, β₂-agonists. Topical/Transdermal: slow, sustained absorption through skin (stratum corneum = rate-limiting barrier). Examples: Nicotine patch, Fentanyl patch. Intramuscular/Subcutaneous: bypasses GI barriers, faster than oral (IM > SC in rate).
- 9Drug Distribution – Tissue Permeability: After absorption, drug distributes from blood to tissues through capillary walls. Factors: (1) Blood flow: highly perfused organs (heart, liver, kidney, brain) receive drug first → equilibrate quickly. Poorly perfused (fat, bone, resting muscle) → slow equilibration. (2) Capillary permeability: most capillaries have intercellular pores → small molecules pass freely. Brain capillaries: tight junctions → Blood-Brain Barrier (BBB) → only lipophilic and small molecules cross. Placental barrier: less restrictive than BBB but important for fetal drug exposure. (3) Tissue binding: drug may accumulate in tissues (Chloroquine in liver, Tetracycline in bone/teeth).
- 10Apparent Volume of Distribution (Vd): Vd = Dose / C₀ (for IV bolus). Vd is the hypothetical volume in which the total amount of drug would need to be uniformly distributed to produce the observed plasma concentration. It is NOT a real physiological volume — it’s a proportionality constant. Interpretation: Vd ≈ 3 L (plasma volume) → drug confined to plasma (highly protein bound — Warfarin, Vd ≈ 8 L). Vd ≈ 14 L (extracellular fluid) → drug distributes into interstitial fluid. Vd ≈ 42 L (total body water) → drug distributes throughout body water. Vd >> 42 L → drug extensively bound to tissues (Chloroquine Vd ≈ 13,000 L — sequestered in tissues). Clinical significance: large Vd → drug cannot be efficiently removed by hemodialysis.
- 11Plasma Protein Binding: Drugs bind reversibly to plasma proteins. Primary binding protein: Albumin (binds acidic drugs — Warfarin, Phenytoin, NSAIDs). α₁-Acid Glycoprotein (AAG): binds basic drugs (Lidocaine, Propranolol, Quinidine). Equilibrium: Drug + Protein ⇌ Drug-Protein Complex. Only FREE (unbound) drug is pharmacologically active (can cross membranes, reach receptors, be metabolized/excreted). Fraction unbound (fu) = Cu/Ct. Highly protein-bound drugs (>90%): Warfarin (99%), Phenytoin (90%), Diazepam (99%).
- 12Factors Affecting Protein Binding: (1) Drug concentration: at high drug levels → binding sites saturate → ↑free fraction (nonlinear). (2) Protein concentration: hypoalbuminemia (liver disease, nephrotic syndrome, malnutrition) → ↓binding → ↑free drug → ↑effect/toxicity. (3) Drug-drug displacement: Drug A displaces Drug B from binding site → ↑free Drug B → transient ↑effect. Example: Warfarin displaced by Phenylbutazone → ↑free Warfarin → bleeding risk. (4) Pathological conditions: uremia → endogenous substances compete for binding sites → ↑free drug. (5) Age: neonates have lower albumin and AAG → ↑free fraction.
- 13Kinetics & Clinical Significance of Protein Binding: Kinetics: binding follows Law of Mass Action. At low drug concentrations → linear (first-order) binding. At high concentrations → saturation (zero-order). Association constant (Ka) = [DP]/([D][P]). Number of binding sites (n) and Ka determined by Scatchard plot: r/[D] = nKa − rKa (linear plot). Clinical significance: (1) Drug-drug interactions (displacement). (2) Disease states altering PB → ↑toxicity at normal doses (Phenytoin in uremia). (3) Therapeutic drug monitoring must measure FREE drug for highly protein-bound drugs. (4) Pregnancy: ↑blood volume → hemodilution → ↓albumin → ↑free fraction. (5) Only free drug is available for metabolism and excretion → PB affects half-life and clearance.
Learning Objectives
Exam Prep Questions – Pharmacokinetics Concepts
Q1. If weak acids are unionized in the stomach, why does most drug absorption occur in the intestine?
Although weak acidic drugs such as Aspirin remain mostly unionized in the acidic environment of the stomach, the majority of drug absorption actually occurs in the small intestine. This happens because the intestine provides several physiological advantages for drug uptake.
First, the surface area of the intestine is extremely large (around 200 m²) due to the presence of villi and microvilli, while the stomach has a much smaller surface area of about 1 m². Second, drugs stay in the intestine for a longer period (3–5 hours) compared to the stomach, where gastric emptying usually occurs within 30–60 minutes. Third, the intestine has a rich blood supply through the mesenteric circulation, which maintains a concentration gradient that favors drug diffusion into the bloodstream.
Even though weak acids become more ionized at the slightly alkaline intestinal pH, a small fraction remains unionized, and the massive intestinal surface area compensates for the lower proportion of unionized drug. Therefore, in real physiological conditions, the small intestine becomes the primary site of drug absorption, showing that the classical pH-partition theory is only a simplified explanation.
Q2. Why can a drug have a Volume of Distribution (Vd) greater than total body water?
The Volume of Distribution (Vd) is an apparent or theoretical volume, not a real anatomical volume in the body. It is calculated using the pharmacokinetic equation:
Vd = Dose / Plasma Drug Concentration (Cp)
If a drug extensively distributes into body tissues such as fat, muscle, organs, or intracellular compartments, only a very small amount remains in the plasma. Because the plasma concentration becomes very low, the calculated value of Vd becomes very large, sometimes much greater than total body water (about 42 L in adults).
This large Vd indicates extensive tissue binding rather than actual physical distribution in such a large volume. For example, Chloroquine has an extremely high Vd of approximately 13,000 L because it accumulates strongly in tissues such as the liver, spleen, and melanin-containing tissues. Similarly, Digoxin has a Vd of around 500 L due to its strong binding to cardiac muscle tissues.
Thus, a very large Vd reflects extensive tissue sequestration and low plasma drug concentration.
Q3. What happens when a highly protein-bound drug is displaced by another drug?
Many drugs bind to plasma proteins such as albumin in the bloodstream. When one drug displaces another drug from these protein-binding sites, the free (unbound) concentration of the displaced drug temporarily increases. Since only the free fraction of a drug is pharmacologically active, this can lead to a temporary increase in drug effect and potential toxicity.
However, the body usually compensates quickly. The increase in free drug concentration leads to faster metabolism in the liver and increased renal excretion, eventually establishing a new steady state. As a result, the total plasma drug concentration decreases, while the free drug concentration returns close to its original level.
Clinically significant displacement interactions are mainly observed when the affected drug:
Is highly protein-bound (more than 90%)
Has a narrow therapeutic index
Is given in high doses or intravenously
Examples of drugs where this interaction can be clinically important include Warfarin and Phenytoin.