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

Drug absorption from the gastrointestinal tract (GIT) is the process by which a drug proceeds from the site of administration to the site of measurement within the body. The primary mechanisms involved are as follows:

1. Passive Diffusion: This is the most common mechanism, where the drug moves from an area of higher concentration to an area of lower concentration. It is a non-energy-dependent, non-saturable process that follows Fick's first law of diffusion. It is favored by small, lipophilic, and unionized drug molecules.
2. Carrier-Mediated Transport: This involves specialized membrane proteins that facilitate the movement of drugs that are too polar or large to diffuse passively. It includes Facilitated Diffusion (down a concentration gradient, no energy required) and Active Transport (against a concentration gradient, requiring ATP and specific carrier proteins). These processes are saturable and subject to competitive inhibition.
3. Vesicular Transport: This includes Endocytosis (pinocytosis or phagocytosis), where the cell membrane engulfs the drug molecule to form a vesicle that enters the cell. This mechanism is significant for the absorption of high-molecular-weight substances, proteins, and fat-soluble vitamins.
4. Paracellular Transport: This involves the movement of drug molecules through the aqueous-filled junctions (tight junctions) between adjacent epithelial cells. It is primarily restricted to small, hydrophilic molecules and is limited by the size of the junctional pores.
5. Ion-Pair Transport: Highly ionized drugs that cannot cross the lipid membrane can form a neutral complex with an endogenous ion of opposite charge (e.g., mucin). This neutral ion-pair complex is lipophilic enough to pass through the membrane via passive diffusion.

Factors influencing these mechanisms include the physicochemical properties of the drug (molecular weight, lipophilicity, pKa), the physiological state of the GIT (pH, surface area, blood flow, and gastric emptying rate), and the presence of transporters or efflux pumps like P-glycoprotein.

Drug absorption is the process of movement of an unchanged drug from the site of administration to the systemic circulation. It is a critical pharmacokinetic parameter that determines the onset, intensity, and duration of the drug's therapeutic effect.

The factors affecting drug absorption are broadly classified into physico-chemical and biological factors:

1. Physico-chemical factors:

• Drug Solubility and Dissolution Rate: According to the Noyes-Whitney equation, the dissolution rate is the rate-limiting step for the absorption of poorly water-soluble drugs (BCS Class II and IV).
• Particle Size: Reducing particle size increases the surface area, which enhances the dissolution rate and consequently the absorption of hydrophobic drugs.
• Polymorphism and Amorphous Form: Different crystalline forms exhibit varying solubility; metastable amorphous forms generally show higher solubility than stable crystalline forms.
• Lipophilicity (Partition Coefficient): A drug must have sufficient lipophilicity to cross the lipid bilayer of cell membranes, but excessive lipophilicity may prevent it from dissolving in the aqueous environment of the GI tract.
• pKa and pH Partition Hypothesis: Weakly acidic or basic drugs exist in equilibrium between ionized and unionized forms. Only the unionized, lipid-soluble form can readily permeate biological membranes.

2. Biological factors:

• Gastrointestinal pH: The pH varies along the GI tract (stomach pH 1-3, small intestine pH 6-7.5), influencing the ionization state of drugs based on their pKa.
• Gastric Emptying Rate: Since the small intestine is the primary site of absorption due to its large surface area, rapid gastric emptying generally increases the rate of drug absorption.
• Intestinal Motility: Increased motility reduces the residence time of the drug in the absorption window, potentially decreasing bioavailability.
• Presystemic Metabolism: Drugs may undergo degradation by luminal enzymes, gut wall enzymes (e.g., CYP3A4), or first-pass hepatic metabolism, which reduces the fraction of drug reaching systemic circulation.
• Physiological Surface Area: The presence of villi and microvilli in the small intestine provides a massive surface area, significantly facilitating the absorption process compared to the stomach.