ADME Q3 2025 Exam Study Guidelines PDF

ADME Q3 2025 Study guide for Exam 2 Absorption and bioavailability 1. Define and explain the four components of Pharmacokinetics: absorption, distribution, metabolism, excretion. a. Absorption: The transfer of a drug from the site of administration into the...

ADME Q3 2025 Study guide for Exam 2 Absorption and bioavailability 1. Define and explain the four components of Pharmacokinetics: absorption, distribution, metabolism, excretion. a. Absorption: The transfer of a drug from the site of administration into the bloodstream. i. Influenced by drug formulation, route of administration, solubility, pH, and presence of food. ii. Oral drugs undergo disintegration and dissolution before absorption. iii. Bioavailability (F) measures the fraction of drug reaching systemic circulation. b. Distribution: The process by which a drug is transported from the bloodstream to tissues and organs. i. Affected by lipophilicity, plasma protein binding, blood flow, and membrane permeability. ii. Volume of Distribution (Vd): A pharmacokinetic parameter that describes the apparent distribution of a drug within the body. c. Metabolism (Biotransformation): The chemical alteration of a drug, primarily occurring in the liver. i. Phase I reactions: Oxidation, reduction, hydrolysis (CYP450 enzymes). ii. Phase II reactions: Conjugation with glucuronic acid, sulfate, acetylation (more water-soluble for excretion). iii. First-pass metabolism reduces the bioavailability of orally administered drugs. d. Excretion: The elimination of drugs and their metabolites from the body, primarily via the kidneys. i. Routes: Urine (renal excretion), bile, feces, sweat, breath, and breast milk. ii. Renal excretion: Includes glomerular filtration, active tubular secretion, and reabsorption. iii. Clearance (Cl) measures the efficiency of drug elimination. 2. Draw a plasma concentration-time curve following oral administration of a drug and label Cmax, Tmax and AUC. a. 3. Define and explain the following terms of a plasma level time curve: Cmax, Tmax, AUC. Which of these terms is used to describe the extent of absorption? Does Tmax indicate rate of absorption? a. Cmax: Maximum plasma concentration of the drug. i. Indicate sufficient absorption for therapeutic effect ii. Provide warning for toxic effect iii. Indicate rate of absorption b. Tmax: Time required to reach Cmax (indicative of absorption rate). Short Tmax means faster absorption. c. AUC (Area Under the Curve): Total drug exposure over time, representing the extent of absorption. i. AUC is proportional to the dose, except in non-linear kinetics d. AUC is the parameter used to describe the extent of absorption, while Tmax indicates the rate of absorption. 4. What is absolute and relative bioavailability? Cite equations to determine both absolute and relative bioavailability. a. Absolute Bioavailability (F_abs): Compares the bioavailability of an extravascular (oral, IM, SC) dose to an IV dose (which is always 100% bioavailable). i. b. Relative Bioavailability (F_rel): Compares the bioavailability of one non-IV formulation to another (e.g., two oral formulations). i. 5. Practice solving problems involving estimation of bioavailability of drug formulation with reference to an IV formulation as well as reference to other oral dosage forms. a. 6. What is the bioequivalence of drug products? How is the bioequivalence established for generic products? a. Bioequivalence refers to the comparability of two drug products in terms of bioavailability (rate and extent of absorption). b. Generic and brand-name drugs must demonstrate similar pharmacokinetic profiles. c. Two drug formulations are considered bioequivalent if their: i. Cmax (peak plasma concentration), ii. Tmax (time to peak concentration), and iii. AUC (total drug exposure) fall within 80-125% of the reference product. d. How Bioequivalence is Established for Generic Products i. Conducted via in vivo bioequivalence studies comparing: 1. AUC (extent of absorption) 2. Cmax (rate of absorption) 3. Tmax (rate indicator) ii. Studies typically involve healthy volunteers in a crossover study design. iii. In some cases, in vitro dissolution testing (Biopharmaceutics Classification System - BCS) may be used. 7. Cite reasons why some drugs have less than complete bioavailability when administered orally? What is the alternative route of administration for a drug with very poor oral bioavailability? a. Some orally administered drugs do not achieve 100% bioavailability due to: i. Incomplete Absorption – Factors include: 1. Poor solubility (low dissolution rate)  2. Instability in gastric acid (e.g., penicillin G) 3. Limited permeability across membranes (e.g., certain peptides) 4. Efflux transporters (e.g., P-glycoprotein) reducing absorption ii. First-Pass Metabolism – Before reaching systemic circulation, drugs may be metabolized in: 1. Intestinal enzymes (CYP3A4 in gut wall) 2. Liver metabolism (hepatic first-pass effect) 3. Bacterial metabolism in the GI tract iii. Chemical Degradation – Drugs sensitive to stomach pH (e.g., omeprazole) or enzymatic degradation (e.g., insulin) may be inactivated b. Alternative Route for Poor Oral Bioavailability i. Drugs with very poor oral bioavailability can be administered via: 1. Intravenous (IV) injection (bypasses absorption, 100% bioavailability) 2. Sublingual/Buccal (avoids first-pass metabolism) 3. Transdermal patches (avoids GI degradation) 4. Intramuscular (IM) or Subcutaneous (SC) injections 5. Rectal suppositories (partial avoidance of first-pass metabolism) 8. Explain pre-systemic elimination and hepatic first pass effect. What are the sites where pre-systemic elimination may occur? a. Pre-Systemic Elimination i. The loss of drug before reaching systemic circulation. ii. Occurs in: 1. Gastrointestinal (GI) lumen: Enzymatic/metabolic degradation. 2. Intestinal wall: CYP3A4-mediated metabolism. 3. Liver (Hepatic First-Pass Effect): Drug undergoes metabolism before entering systemic circulation. 4. Lung & Plasma Enzymes: Certain drugs are degraded in the lung (e.g., propofol) or blood plasma (e.g., esterase enzymes for prodrugs like aspirin). b. Hepatic First-Pass Effect i. Loss of drug during first passage through the liver ii. Drugs absorbed from the GI tract enter the hepatic portal circulation before reaching systemic circulation. iii. The liver metabolizes a portion of the drug, reducing its bioavailability. iv. Drugs with high first-pass metabolism include propranolol, morphine, nitroglycerin, and lidocaine. 9. Give equations to show the relationship between hepatic extraction ratio, hepatic clearance and blood flow. Given the hepatic extraction ratio and blood flow to the liver, how will you determine the fraction absorbed? a. Hepatic Extraction Ratio (ER): i. ii. CA= Drug Concentration in arterial blood iii. Cv= Drug concentration in venous blood iv. Measures the fraction of drug removed by the liver b. Hepatic Clearance (ClH): i. ii. Q= Hepatic blood flow (1.5 L/min) iii. ER= Hepatic extraction ratio iv. Represents the volume of plasma cleared of drug by the liver per unit time c. Fraction Absorbed into Systemic Circulation (Bioavailability, F) i. ii. If ER is high (>0.8), oral bioavailability is low, requiring alternative administration. iii. If ER is low ( 0.8) → Low oral bioavailability (e.g., Morphine, Nitroglycerin) c. Low ER (< 0.2) → High oral bioavailability (e.g., Diazepam, Phenytoin) d. Examples: i. Morphine (ER = 0.75) → F=1−0.75=0.25F = 1 - 0.75 = 0.25F=1−0.75=0.25 (Low bioavailability) ii. Propranolol (ER = 0.90) → F=1−0.90=0.10F = 1 - 0.90 = 0.10F=1−0.90=0.10 (Very low bioavailability)  iii. Phenytoin (ER = 0.1) → F=1−0.1=0.90F = 1 - 0.1 = 0.90F=1−0.1=0.90 (High bioavailability) e. Drugs with high ER require higher oral doses or alternative routes (IV, sublingual, transdermal). 12. Cite and briefly describe various mechanisms of absorption of a drug given orally. Distinguish between paracellular and transcellular absorption of drugs. a. Passive Diffusion i. Diffusion through lipoidal bilayer ii. Depends on size, concentration, polarity, degree of ionization, partition coefficient, surface area of absorption site, blood flow iii. Most common mechanism iv. Drug moves from high to low concentration across membranes. v. No energy required. b. Facilitated Diffusion i. Carrier proteins assist movement without energy. ii. Example: Glucose transporters for Metformin (OCT1 transporter). c. Active Transport i. Carrier-mediated, requires energy (ATP). ii. A transport protein is involved iii. Moves against concentration gradient. iv. Example: L-Dopa (uses amino acid transporter). d. Endocytosis i. Used by large molecules (e.g., Vitamin B12, nanoparticles). e. Paracellular vs. Transcellular absorption i. Paracellular: 1. Passage of drugs through the junctions between the cells. 2. It is dependent on the size of the junction and on the size of the drug molecule. 3. In sensitive tissues, such as the central nervous system (CNS), the retina, the placenta, and the testes, the capillary epithelial membrane is very tightly knit and limits paracellular diffusion. 4. Some peptides are transported by the paracellular route. ii. Transcellular: 1. The ease of transcellular diffusion is determined by a drug's permeability across the lipophilic matrix of the membrane. 2. Depends on the lipophilicity, polarity, and size of the drug molecule. 3. A drug's lipophilicity is probably the most important determinant of permeability. 4. A drug's lipophilicity is traditionally assessed by measuring its distribution between the immiscible phases of n-octanol and water  iii. Tightly joined tissues (BBB, placenta) limit paracellular absorption. iv. Lipophilicity increases transcellular absorption. 13. Describe the characteristics of passive and active absorption of drugs. a. b. Active transport is saturable (limited transporter availability). c. Passive diffusion is non-saturable (continues as long as concentration gradient exists). 14. What are the factors governing diffusion of a drug across biological membranes? a. Diffusion follows Ficks Law: i. ii.dQ/dt = rate of diffusion of a drug iii.R= Partition coefficient of the drug between the membrane iv. and aqueous phase v. D= Diffusion coefficient of the drug, a function of solubility in the membrane and molecular size vi. A = Surface area of the membrane where transfer occurs i. h = thickness of the membrane b. RDA and h are constant for a given membrane. Can be combined into one constant, the permeability factor P dQ/dt = P (C1-C2). c. Key factors Affecting Drug Diffusion i. Lipid Solubility: 1. Lipophilic drugs cross membranes easily (e.g., Diazepam). 2. Hydrophilic drugs require transporters (e.g., Glucose, Amino Acids). ii. Molecular Size 1. Smaller molecules diffuse faster. 2. Larger drugs (Biologics) require active transport. iii. Ionization & pH (Henderson-Hasselbalch Equation): 1. Unionized (non-polar) form = Better absorption. 2. Weak acids absorb in acidic pH (stomach). 3. Weak bases absorb in alkaline pH (intestine).  iv. Membrane Permeability: 1. High permeability → faster diffusion. 2. Blood-Brain Barrier (BBB) restricts large, hydrophilic molecules. v. Surface Area of Absorption Site: 1. Intestinal villi & microvilli increase absorption. 2. Large surface area = faster diffusion. vi. Blood Flow & Perfusion: 1. More perfusion = faster absorption. 2. Poor circulation (e.g., shock) slows drug uptake. 15. How the Henderson-Hasselbalch equation is applied to predict absorption of weak acids and bases. If the pka of drug and the pH are numerically the same, what would be the ratio of ionized to unionized? a. The Henderson-Hasselbalch equation is used to predict the degree of ionization of weak acids and bases, which affects their absorption across biological membranes. b. Equations: i. ii. Weak Acids: 1. iii. Weak Bases: 1. c. Prediction of Absorption: i. Unionized drugs (lipophilic) cross membranes easily. ii. Ionized drugs (hydrophilic) do not cross easily and require transporters. d. Examples: i. Absorption of a Weak Acid (pKa = 4) in the Stomach (pH = 1) 1. 2. 99.9% of the drug is unionized and can be absorbed ii. If pKa= pH  1. 2. 1:1 ratio, meaning 50% ionized and 50% unionized 16. What are the different types of membrane bound transporters involved in the absorption of drugs from the g.i.t.? Discuss the role of transporters in the absorption of drugs with examples. a. Uptake Transporters (Increase Absorption) i. Organic Anion Transporting Polypeptides (OATP1, OATP2) ii. Peptide Transporters (PEPT1, PEPT2) iii. Organic Cation Transporters (OCT1, OCT2) iv. Examples: 1. OATP1B1 transports Fexofenadine (antihistamine). 2. PEPT1 helps absorb penicillins, cephalosporins. b. Efflux Transporters (Decrease Absorption) i. P-Glycoprotein (P-gp) ii. Multidrug Resistance Proteins (MRP2, MRP4) iii. Examples: 1. P-gp actively pumps digoxin and paclitaxel out of cells. 2. MRP2 limits absorption of methotrexate. c. Role of Transporters in Drug Absorption i. Increase absorption (e.g., PEPT1 for β-lactam antibiotics). ii. Limit absorption (e.g., P-gp efflux of chemotherapy drugs). iii. Affect drug-drug interactions (e.g., grapefruit juice inhibits OATP1, reducing fexofenadine absorption by 50%). 17. Distinguish between active and facilitated absorption of drugs. a. b. Facilitated transport does not require ATP, but active transport does. c. Active transport moves against a gradient, while facilitated transport follows a gradient. 18. What are uptake and efflux transporters? Give two examples of each. a. Membrane transporters regulate drug absorption, distribution, and elimination.  i. Uptake Transporters (Enhance Absorption) 1. Transport drugs into cells from the gut, liver, and kidney. 2. Examples: a. OATP1B1 (Organic Anion Transporting Polypeptide) – Absorbs statins (atorvastatin) into hepatocytes. 3. PEPT1 (Peptide Transporter 1) – Absorbs cephalosporins and ACE inhibitors (Captopril). ii. Efflux Transporters (Reduce Absorption) 1. Actively pump drugs out of cells, limiting absorption. 2. Examples: a. P-glycoprotein (P-gp) – Pumps out digoxin, paclitaxel. b. MRP2 (Multidrug Resistance Protein 2) – Limits methotrexate absorption. b. Clinical Impact of Transporters: i. Inhibition of P-gp (by Cyclosporine) increases digoxin absorption. ii. OATP inhibition (by Grapefruit Juice) reduces statin absorption. 19. Discuss the role of p-glycoprotein and the effect of its induction/inhibition in the absorption of drugs with examples. a. What is P-Glycoprotein? i. P-Glycoprotein (P-gp) is an efflux transporter found in the intestinal lining, liver, kidney, and blood-brain barrier. ii. It actively pumps drugs out of cells, reducing drug absorption and increasing drug elimination. b. Effects on Drug Absorption i. P-gp limits oral drug absorption by pumping drugs back into the intestinal lumen before they reach systemic circulation. ii. High P-gp activity → Lower drug bioavailability. iii. Low P-gp activity → Higher drug absorption and potential toxicity. c. Effect of P-gp Induction i. Induction increases P-gp expression, leading to decreased drug absorption and lower bioavailability. ii. Example: Rifampin (Rifampicin) induces P-gp, reducing digoxin absorption. d. Effect of P-gp Inhibition i. Inhibition decreases P-gp activity, leading to increased drug absorption and higher plasma concentrations. ii. Example: Cyclosporine inhibits P-gp, increasing the absorption of paclitaxel. e. Clinical Significance i. P-gp inhibitors (e.g., Verapamil, Cyclosporine) can enhance drug bioavailability, potentially leading to toxicity. ii. P-gp inducers (e.g., Rifampin, St. John’s Wort) can lower drug levels, reducing effectiveness. 20. What is the mechanism of a change in oral bioavailability of some drugs by grapefruit juice? Cite examples. a. Grapefruit juice inhibits intestinal CYP3A4 and OATP transporters, affecting drug absorption. b. Mechanisms: i. Inhibition of CYP3A4 (Intestinal Metabolism) 1. Grapefruit juice inhibits CYP3A4 enzymes in the gut, leading to higher plasma drug concentrations. 2. Example: Felodipine (a calcium channel blocker) → Increased plasma concentration → Higher risk of hypotension. ii. Inhibition of OATP (Uptake Transporter) 1. OATP1A2 inhibition decreases drug absorption. 2. Example: Fexofenadine (antihistamine) → Lower absorption → Reduced therapeutic effect. c. Drugs Affected by Grapefruit Juice i. d. Clinical Advice: i. Patients should avoid grapefruit juice if taking drugs metabolized by CYP3A4 or transported by OATP. 21. How does dairy products influence absorption of drugs? Cite examples. a. Dairy products (milk, cheese, yogurt) contain calcium, which can interact with certain drugs and reduce their absorption. b. Mechanism: i. Formation of Insoluble Complexes (Chelation) 1. Calcium binds to certain drugs, forming an insoluble complex that cannot be absorbed. 2. Example: Tetracyclines & Fluoroquinolones (Ciprofloxacin, Doxycycline). 3. Effect: Reduced absorption → Decreased effectiveness. ii. Alteration of Gastric pH 1. Dairy products increase stomach pH, affecting the solubility of certain drugs. 2. Example: Itraconazole (antifungal) requires an acidic environment for absorption. 3. Effect: Reduced absorption → Decreased antifungal effect. iii. Drugs Affected by Dairy Products  1. iv. Clinical Advice: 1. Avoid dairy products within 2 hours before or after taking affected drugs. 22. Cite an application of the BCS classification of drugs. a. The BCS classification categorizes drugs based on solubility and permeability, guiding bioavailability predictions and regulatory approvals. b. BCS Classes i. c. Application: i. Bioequivalence (Biowaiver) 1. Class I drugs (high solubility, high permeability) can be approved without in vivo bioavailability studies. 2. Example: Metoprolol IR tablets can get FDA approval based on dissolution testing. ii. Formulation Development 1. Class II drugs (low solubility, high permeability) require enhanced solubility techniques (e.g., nanocrystals). 2. Example: Ibuprofen tablets use solubilizing agents for better absorption. iii. Predicting Food Effects 1. Class III drugs (high solubility, low permeability) have absorption influenced by gut transporters. 2. Example: Atenolol absorption is affected by food intake. 23. Which class of drugs may be waived by the FDA from the requirement of bioavailability evaluation in the human? Cite exceptions. a. The FDA can waive in vivo bioavailability studies for Biopharmaceutics Classification System (BCS) Class I drugs.  b. BCS Class I drugs have high solubility and high permeability, meaning they are well absorbed and not affected by formulation differences. c. Criteria for Biowaiver (BCS Class I Drugs) i. High solubility: Dissolves completely in 250 mL or less of aqueous medium (pH 1.2 - 6.8). ii. High permeability: ≥ 85% of the dose is absorbed in humans. iii. Rapid dissolution: ≥ 85% dissolves within 30 minutes in standard dissolution media. d. Exceptions (Biowaiver Not Allowed) i. Narrow therapeutic index (NTI) drugs, e.g. Warfarin, Digoxin, Phenytoin. ii. Modified-release formulations (only immediate-release (IR) forms are eligible). iii. Drugs with complex absorption mechanisms (e.g., transporters, food effects). iv. Different esters, isomers, or derivatives of a drug. 24. Which class of drugs in the BCS system exhibit dissolution-rate limited absorption? a. BCS Class II drugs (Low solubility, High permeability) exhibit dissolution- rate limited absorption. b. Since they dissolve slowly, their rate of absorption depends on how fast the drug dissolves in the gastrointestinal tract. c. Examples: Ibuprofen, Ketoconazole, Griseofulvin. d. Key Challenge: i. Increasing solubility is necessary to improve bioavailability (e.g., using nanoparticles, salt forms, surfactants). 25. What are the specifications for a drug substance to be considered as highly soluble? a. The highest dose strength dissolves completely in ≤ 250 mL of aqueous media. b. The pH range for solubility testing is 1.2 - 6.8 (simulating gastric and intestinal conditions). c. The solubility testing should be performed at 37°C (physiological temperature). d. The drug should remain soluble at all physiologically relevant pH levels. e. Example Drugs: i. Metoprolol, Propranolol, Atenolol (All BCS Class I or III drugs) 26. What are the specifications for a drug substance to be considered as highly permeable? a. ≥ 85% of the administered dose is absorbed in humans. b. It is extensively metabolized (if it undergoes first-pass metabolism). c. In vivo or in vitro studies demonstrate high permeability across biological membranes. d. Methods for permeability testing include: i. Human mass balance studies (urinary excretion of unchanged drug ≥ 85%). ii. Caco-2 cell permeability studies (in vitro human intestinal model). iii. Animal models for permeability testing. e. Example Drugs: i. Propranolol, Metoprolol, Verapamil (BCS Class I – High solubility, High permeability).