JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD B. Pharmacy III Year BIOPHARMACEUTICS AND PHARMACOKINETICS Previous Question Paper (August/September -2021 - R17)

Drug absorption from the gastrointestinal tract (GIT) is significantly influenced by the physico-chemical properties of the drug molecule, which dictate its ability to cross biological membranes. The primary factors include:

1. Drug Solubility and Dissolution Rate: According to the Noyes-Whitney equation, the dissolution rate is the limiting step for the absorption of poorly water-soluble drugs (BCS Class II and IV). Factors such as particle size, crystal form (polymorphism), and salt formation directly affect solubility.

2. Molecular Size and Weight: Smaller molecules generally permeate biological membranes more easily via passive diffusion. Drugs with a molecular weight greater than 500 Daltons often show reduced permeability.

3. Lipophilicity (Partition Coefficient): The lipid bilayer of the cell membrane favors the transport of lipophilic drugs. The partition coefficient (log P) is a measure of a drug's lipophilicity; an optimal log P value is required to balance solubility and membrane permeability.

4. Degree of Ionization (pH-Partition Hypothesis): Most drugs are weak acids or weak bases. According to the pH-partition theory, only the unionized form of a drug is lipid-soluble and can permeate the membrane. The degree of ionization is determined by the pKa of the drug and the pH of the GI fluid, as described by the Henderson-Hasselbalch equation:

5. Chemical Stability and Degradation: Some drugs are unstable in the acidic environment of the stomach (e.g., acid-labile drugs like penicillin G or erythromycin) or are susceptible to enzymatic degradation by GI enzymes, which reduces the amount of drug available for absorption.

6. Complexation and Adsorption: The formation of complexes between a drug and other components in the GI tract (e.g., metal ions, food components, or excipients) can alter the effective concentration of the free drug, often decreasing its absorption rate.

7. Surfactant Effects: Naturally occurring surfactants like bile salts in the GIT can increase the solubility and dissolution of hydrophobic drugs by forming micelles, thereby enhancing their absorption.

Drug absorption is the process by which a drug proceeds from the site of administration to the site of measurement (usually systemic circulation). The mechanism of transport across biological membranes depends on the physicochemical properties of the drug and the nature of the membrane.

The primary mechanisms of drug absorption are:

1. Passive Diffusion: This is the most common mechanism, where the drug moves from an area of high concentration to low concentration. It is a non-saturable, non-energy-requiring process driven by the concentration gradient. It follows Fick's First Law of Diffusion. Examples include lipid-soluble drugs like aspirin and ethanol.
2. Pore Transport (Convective Transport): Small, water-soluble molecules pass through aqueous-filled channels or pores in the membrane. This is restricted to molecules with a low molecular weight (typically less than 100-200 Da). Examples include urea, water, and small ions like lithium.
3. Facilitated Diffusion: This involves a carrier protein that facilitates the movement of a drug across the membrane down its concentration gradient. It does not require energy (ATP) and is a saturable process. An example is the absorption of Vitamin B12 via intrinsic factor or glucose transport via GLUT transporters.
4. Active Transport: This process moves drugs against a concentration gradient using carrier proteins and metabolic energy (ATP). It is highly selective, saturable, and subject to competitive inhibition. Examples include the absorption of levodopa, amino acids, and certain vitamins.
5. Vesicular Transport (Endocytosis/Exocytosis): This mechanism involves the engulfment of drugs by the cell membrane to form vesicles. Pinocytosis (cell drinking) or phagocytosis (cell eating) allows the transport of large molecules, proteins, or lipid-soluble vitamins. Examples include the absorption of fat-soluble vitamins (A, D, E, K) and insulin.
6. Ion-Pair Transport: Highly ionized drugs that cannot cross the lipid membrane can form a neutral complex with an endogenous ion of opposite charge, creating an ion pair that is lipid-soluble and can diffuse through the membrane. An example is the absorption of propranolol with oleic acid.