JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD B. Pharmacy III PHARMACOLOGY-I Previous Question Paper (October/November-2020 - R17)

Drug metabolism, primarily occurring in the liver, is the process of biotransformation where lipophilic drugs are converted into more polar, hydrophilic, and ionized metabolites to facilitate their excretion from the body. Its importance includes: terminating the pharmacological activity of drugs, promoting renal excretion by reducing tubular reabsorption, and potentially activating prodrugs into their active forms. It also plays a critical role in detoxification, though it can occasionally lead to bioactivation into toxic or carcinogenic intermediates.

Metabolic reactions are categorized into two phases:

Phase-I Reactions (Functionalization): These reactions introduce or expose a functional group (-OH, -NH2, -SH, or -COOH) on the drug molecule, making it slightly more polar. These reactions are primarily mediated by the cytochrome P450 (CYP450) monooxygenase system located in the endoplasmic reticulum. Key reactions include:

• Oxidation: The most common reaction, including hydroxylation, N-dealkylation, O-dealkylation, and deamination.
• Reduction: Typically occurs in low-oxygen environments, involving the reduction of azo or nitro groups.
• Hydrolysis: Mediated by esterases and amidases, breaking down esters and amides into acids and alcohols.

Phase-II Reactions (Conjugation): These reactions involve the attachment of an endogenous, highly polar, water-soluble substrate to the drug or its Phase-I metabolite. This process usually results in pharmacological inactivation and rapid renal or biliary excretion. Key reactions include:

• Glucuronidation: The most common conjugation pathway, catalyzed by UDP-glucuronosyltransferase (UGT), which transfers glucuronic acid from UDP-glucuronic acid to the drug.
• Acetylation: Catalyzed by N-acetyltransferase (NAT) using Acetyl-CoA as a cofactor.
• Sulfation: Catalyzed by sulfotransferases (SULT) using PAPS (3'-phosphoadenosine-5'-phosphosulfate) as the sulfate donor.
• Glutathione Conjugation: Catalyzed by glutathione S-transferase (GST), which is vital for detoxifying reactive electrophilic compounds.
• Methylation: Catalyzed by methyltransferases, typically reducing the polarity of the drug.

Bioavailability is defined as the fraction of an administered dose of an unchanged drug that reaches the systemic circulation. It serves as a measure of the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of drug action.

Factors affecting drug absorption are categorized into pharmaceutical, physiological, and physicochemical factors:

• Physicochemical factors: Drug solubility and dissolution rate are primary determinants; only drugs in solution can be absorbed. The pH partition theory dictates that weak acids are better absorbed in the acidic environment of the stomach, while weak bases are better absorbed in the intestine. Particle size and crystalline form (polymorphism) also significantly influence the dissolution rate.
• Physiological factors: The gastrointestinal surface area and transit time are critical; the small intestine provides a larger surface area and longer residence time compared to the stomach. Gastric emptying rate influences the speed of drug arrival at the absorption site. Blood flow to the gastrointestinal tract maintains the concentration gradient necessary for passive diffusion.
• Pharmaceutical factors: The type of dosage form (e.g., solution, suspension, tablet, or capsule) and the presence of excipients (binders, disintegrants, lubricants) dictate the disintegration and dissolution profile.
• First-pass metabolism: Drugs administered orally may undergo significant metabolism in the liver or gut wall before reaching systemic circulation, which reduces the absolute bioavailability.
• Drug interactions: The presence of food or other co-administered drugs can alter gastric pH, complex with the drug to prevent absorption, or change gastrointestinal motility, thereby modifying the rate and extent of absorption.