# Drug Absorption, Bioavailability and Distribution for NEET PG Pharmacology: pKa, First-Pass, AUC, Volume of Distribution Source: https://tracknation.in/story/drug-absorption-bioavailability-and-distribution-for-neet-pg-pharmacology-pka-first-pass-auc-volume-of-distribution (TrackNation β€” free UPSC notes with PYQs) > NEET PG Pharmacology: how drugs cross membranes, why pKa and pH decide ionisation, what changes oral absorption, first-pass metabolism, bioavailability and AUC, bioequivalence, volume of distribution with worked calculations, protein binding, redistribution and the blood-brain barrier, with a diagram, hooks, MCQs and cards. ## Start Here 🎯 **Exam priority: High.** *Pharmacokinetics questions are short and mostly logic: an ionisation scenario, a volume of distribution sum, or which drug is displaced. Learn the rule and the calculation.* CBME mapping: **PH 1.4, PH 1.5, PH 1.6**. Pharmacokinetics is what the body does to a drug; pharmacodynamics is what the drug does to the body. ## Crossing Membranes A drug must be in solution to be absorbed, and unless given IV it must cross cell membranes to reach the circulation. | **Mechanism** | **Energy** | **Against gradient?** | **Point to remember** | | Passive diffusion | No | No | Most drugs; favours lipid-soluble, small, un-ionised molecules | | Facilitated diffusion | No | No | Carrier-mediated; for example glucose | | Active transport | Yes | Yes | Selective; for drugs resembling ions, vitamins, sugars, amino acids | | Pinocytosis | Yes | β€” | Vesicle engulfs fluid or particles; more relevant for protein drugs | **Passive diffusion** goes faster with a steeper concentration gradient, higher lipid solubility, smaller size, lower ionisation and larger surface area. ## Ionisation: pH and pKa Most drugs are weak acids or bases. The **un-ionised** form crosses membranes; the ionised form does not. **pKa** is the pH at which the two forms are equal. | **Setting** | **Weak acid (e.g. aspirin)** | **Weak base (e.g. quinidine)** | | pH below pKa | Mostly **un-ionised** | Mostly **ionised** | | pH above pKa | Mostly ionised | Mostly un-ionised | | pKa 4.4 at stomach pH 1.4 | Un-ionised : ionised = 1000 : 1 | Mostly ionised | | pKa 4.4 at plasma pH 7.4 | Un-ionised : ionised = 1 : 1000 | β€” | **The rule**: acids stay un-ionised in acid, bases stay un-ionised in base. Each step of 1 pH unit away from pKa changes the ratio tenfold, which is why 3 units gives 1000 to 1. **The catch**: even though aspirin is un-ionised in the stomach, most absorption of any oral drug happens in the **small intestine**, because its surface area is larger and its membranes are more permeable. ## Oral and Other Routes - **Gastric emptying** is often the rate-limiting step. Food, especially fat, slows it. Drugs that delay emptying, such as parasympatholytics, slow the absorption of other drugs. - **Food effects**: raises the extent of absorption of griseofulvin; lowers it for penicillin G, which is degraded in the stomach. - **Dissolution** can be the rate-limiting step for solid forms. - **Peptides** such as insulin are destroyed in the gut and are not given orally. - **Buccal and sublingual**: thin, vascular mucosa; holding the drug in place improves absorption. - **IV** enters the circulation directly. **IM and subcutaneous** doses must still cross membranes. - **Controlled-release** forms reduce dosing frequency and smooth out plasma levels. Crushing them can be dangerous. **Transdermal** forms release drug over long periods. ## Bioavailability *AUC tells you how much drug got in. Peak time tells you how fast.* **Bioavailability** is the extent and rate at which the active drug reaches the systemic circulation: amount absorbed Γ· dose. - **Measured by AUC**, the most reliable measure. The peak level can mislead because elimination starts at once. Peak time is the usual index of absorption rate. - **First-pass metabolism** happens in the gut wall and liver before the drug reaches the systemic circulation, and is a common cause of low oral bioavailability. - **Other causes**: poor water solubility, slow absorption, too little time in the gut, and chemical reactions such as **tetracycline binding metal ions** or **digoxin adsorbing to cholestyramine**. | **Term** | **Means** | | Chemical equivalence | Same active drug, same amount; inactive ingredients may differ | | Bioequivalence | Same dose regimen gives equivalent drug levels in plasma and tissues | | Therapeutic equivalence | Same dose regimen gives the same therapeutic and adverse effects | **Therapeutic index** is the ratio of minimum toxic concentration to median effective concentration. Small bioavailability differences matter most for narrow therapeutic index drugs; penicillin's wide index tolerates them. ## Distribution **Apparent volume of distribution (Vd)** = amount of drug in the body Γ· plasma concentration. It is a theoretical volume, not a real fluid compartment. **Worked example**: 1,000 mg gives a plasma level of 10 mg/L. Vd = 1,000 Γ· 10 = **100 L**. That is more than total body water, so the drug must be concentrated in tissues. - **High Vd**: heavily tissue-bound, little left in plasma. - **Low Vd**: stays in the circulation. | **Drug type** | **Binds mainly to** | **Volume of distribution** | **Examples** | | Acidic | Albumin | Small | Warfarin, aspirin | | Basic | Alpha-1 acid glycoprotein, lipoproteins | Large | Amphetamine, meperidine | **Only unbound drug** reaches tissues and acts. Saturation of binding sites is the basis of **displacement interactions**. - **Redistribution**: thiopental enters the brain fast and works fast, then its effect ends within minutes as it moves to poorly perfused fat. Repeated doses accumulate there. - **Tissue storage**: chloroquine reaches levels thousands of times plasma in white cells and liver. - **Blood-brain barrier**: tight capillary endothelium plus an astrocytic sheath. Lipid-soluble drugs enter; polar compounds do not. ## Traps the Examiner Sets - Weak acids are un-ionised in the stomach, but the main absorption site is still the small intestine. - High Vd means low plasma level, not more drug in the blood. - Acidic drugs bind albumin; basic drugs bind alpha-1 acid glycoprotein. - Thiopental's short action comes from redistribution, not metabolism. - AUC measures extent; peak time reflects rate. - Facilitated diffusion uses a carrier but no energy. ## Memory Hooks & Shortcuts *Shortcuts to lock in this article's numbers and lists. Each one only re-packages facts proven above.* - 🧠 **Like stays un-ionised with like** β€” acid in acid, base in base - 🧠 **Three pH units, a thousand to one** β€” each unit away from pKa changes the ratio tenfold - 🧠 **Absorption lives in the small intestine** β€” whatever the drug's charge - 🧠 **AUC = how much, peak time = how fast** β€” extent and rate of absorption - 🧠 **Vd = Dose over Concentration** β€” the only sum you need - 🧠 **Acids to Albumin** β€” the A-A binding pair - 🧠 **Thiopental leaves for fat** β€” redistribution ends its effect ## Rapid-Revision Cards - What the body does to the drug; what the drug does to the body. - Un-ionised, lipid-soluble. - pH at which ionised and un-ionised forms are equal. - Mostly un-ionised. - Mostly ionised. - Small intestine, for acids and bases. - Often gastric emptying. - Needs energy, selective, can go against a gradient. - Carrier, no energy, not against a gradient. - Protein drugs. - Extent and rate of reaching systemic circulation; amount absorbed Γ· dose. - AUC. - Elimination rate equals absorption rate. - In gut wall and liver, before systemic circulation. - Metal ion complex reduces absorption. - Equivalent plasma and tissue levels. - Minimum toxic Γ· median effective concentration. - Amount in body Γ· plasma concentration. - Tissue-bound, low plasma level. - Albumin. - Alpha-1 acid glycoprotein and lipoproteins. - Unbound drug. - Redistribution to fat. - Capillary endothelium + astrocytic sheath. ## Sources *Facts in this article were checked against these documents.* - Overview of Pharmacokinetics; Drug Absorption; Drug Bioavailability; Drug Distribution to Tissues β€” MSD Manual Professional Edition, reviewed 2026 (link) - Competency Based Undergraduate Curriculum, Pharmacology (PH) β€” National Medical Commission, 2024 ## Test Yourself: Practice Questions Twenty-six questions in NEET PG style, including clinical vignettes. ## Practice Questions (NEET PG pattern) *Original questions written in the style of the exam: +4 for a correct answer, βˆ’1 for a wrong one. Every answer was checked against the sources listed above. NEET PG papers are not published by NBEMS, so these are not past-paper questions.* **Q1.** Which form of a drug crosses cell membranes most easily by passive diffusion? - (a) Protein-bound - (b) Large and polar - (c) Ionised, water-soluble - (d) Un-ionised, lipid-soluble **Answer: (d)** β€” The un-ionised form is usually lipid soluble and diffuses readily. **Q2.** A weak acid with a pKa of 4.4 is in gastric fluid at pH 1.4. The ratio of un-ionised to ionised drug is - (a) 1 : 1 - (b) 1 : 1000 - (c) 1000 : 1 - (d) 10 : 1 **Answer: (c)** β€” pH is 3 units below pKa, so the acid is mostly un-ionised: 1000 to 1. **Q3.** pKa is the pH at which a drug is - (a) 50% ionised - (b) bound to albumin - (c) fully un-ionised - (d) fully ionised **Answer: (a)** β€” At pKa, ionised and un-ionised forms are equal. **Q4.** Aspirin is a weak acid. The main site of its absorption is the - (a) stomach - (b) small intestine - (c) colon - (d) mouth **Answer: (b)** β€” Whether acid or base, most absorption occurs in the small intestine, with its larger surface area. **Q5.** Transport that needs energy and can move a drug against a concentration gradient is - (a) active transport - (b) passive diffusion - (c) facilitated diffusion - (d) filtration **Answer: (a)** β€” Active transport is selective and energy-dependent. **Q6.** Glucose crosses membranes faster than its lipid solubility predicts, without using energy. This is - (a) simple diffusion - (b) active transport - (c) facilitated diffusion - (d) pinocytosis **Answer: (c)** β€” A carrier speeds passage without energy expenditure or transport against a gradient. **Q7.** Insulin is not given orally because - (a) it is excreted in bile - (b) it is degraded in the gut - (c) it causes vomiting - (d) it is too lipid soluble **Answer: (b)** β€” Peptide drugs are susceptible to degradation. **Q8.** Taking griseofulvin with a fatty meal - (a) increases its absorption - (b) stops its absorption - (c) has no effect - (d) destroys the drug **Answer: (a)** β€” Food may enhance the extent of absorption of poorly soluble drugs such as griseofulvin. **Q9.** The rate-limiting step for absorption of many oral drugs is - (a) plasma protein binding - (b) gastric emptying - (c) renal clearance - (d) biliary excretion **Answer: (b)** β€” Most absorption occurs in the small intestine, so gastric emptying often limits the rate. **Q10.** A patient crushes a controlled-release tablet because he cannot swallow it. The main concern is - (a) the dose may be released too quickly - (b) no concern at all - (c) the drug becomes inactive - (d) the drug cannot be absorbed **Answer: (a)** β€” Crushing or disturbing a controlled-release form can be dangerous. **Q11.** The most reliable measure of the extent of bioavailability is - (a) peak time - (b) peak concentration - (c) area under the plasma concentration–time curve - (d) half-life **Answer: (c)** β€” AUC is directly proportional to the unchanged drug reaching the circulation. **Q12.** Peak plasma concentration after an oral dose occurs when - (a) half the dose is excreted - (b) absorption has stopped completely - (c) the drug reaches the liver - (d) elimination rate equals absorption rate **Answer: (d)** β€” The peak is reached when the rate of elimination equals the rate of absorption. **Q13.** Metabolism of a drug in the gut wall and liver before it reaches the systemic circulation is - (a) redistribution - (b) phase II conjugation - (c) first-pass metabolism - (d) enterohepatic circulation **Answer: (c)** β€” First-pass metabolism occurs before a drug reaches the systemic circulation. **Q14.** A patient on tetracycline takes antacids and has a poor response. The mechanism is - (a) enzyme induction - (b) complex formation with metal ions - (c) increased renal excretion - (d) protein displacement **Answer: (b)** β€” Tetracycline forms a complex with polyvalent metal ions, reducing absorption. **Q15.** Two brands give equivalent plasma and tissue levels when used in the same regimen. They are - (a) bioequivalent - (b) therapeutically inferior - (c) chemically different - (d) prodrugs **Answer: (a)** β€” Bioequivalence means equivalent drug concentrations in plasma and tissues. **Q16.** A patient gets 500 mg of a drug and the plasma level is 25 mg/L. The apparent volume of distribution is - (a) 20 L - (b) 12.5 L - (c) 0.05 L - (d) 125 L **Answer: (a)** β€” Vd = amount in body Γ· plasma concentration = 500 Γ· 25 = 20 L. **Q17.** A drug is given in a dose of 2,000 mg and gives a plasma level of 2 mg/L. It is most likely - (a) confined to the ECF - (b) not absorbed - (c) confined to plasma - (d) heavily bound in tissues **Answer: (d)** β€” Vd is 1,000 L, far above body volume: the drug is tissue-bound with a low plasma level. **Q18.** Acidic drugs bind mainly to - (a) globulin only - (b) alpha-1 acid glycoprotein - (c) albumin - (d) haemoglobin **Answer: (c)** β€” Acidic drugs bind albumin; basic drugs bind alpha-1 acid glycoprotein and lipoproteins. **Q19.** Which part of a drug in plasma is pharmacologically active? - (a) The total concentration - (b) The fraction in red cells - (c) The unbound fraction - (d) The albumin-bound fraction **Answer: (c)** β€” Only unbound drug is available for passive diffusion to tissues. **Q20.** A single IV dose of thiopental wears off within minutes because of - (a) rapid hepatic metabolism - (b) rapid renal excretion - (c) binding to receptors - (d) redistribution to fat **Answer: (d)** β€” The effect ends as the drug redistributes to slowly perfused fatty tissues. **Q21.** The blood-brain barrier is formed by - (a) the dura mater - (b) the choroid plexus alone - (c) the arachnoid only - (d) brain capillary endothelium and the astrocytic sheath **Answer: (d)** β€” Tight capillary endothelium plus astrocytes. **Q22.** An 80-year-old on long-term phenytoin is admitted malnourished with serum albumin 2.1 g/dL. Her total phenytoin level is in range but she is ataxic. The best explanation is - (a) reduced oral absorption - (b) more unbound (free) phenytoin because albumin is low - (c) phenytoin enzyme induction - (d) a falsely high total level **Answer: (b)** β€” Rapid falls in albumin raise the unbound (active) fraction; phenytoin and warfarin are the classic examples. **Q23.** A man takes digoxin and cholestyramine together each morning, and his digoxin level is low. The mechanism is - (a) enzyme induction - (b) displacement from albumin - (c) increased renal clearance - (d) adsorption of digoxin to cholestyramine in the gut **Answer: (d)** β€” Bioavailability falls when a drug adsorbs to another drug, such as digoxin to cholestyramine; separate the doses. **Q24.** Oral penicillin G is best taken - (a) with a fatty meal to increase absorption - (b) with antacids - (c) on an empty stomach, because food reduces absorption of drugs degraded in the stomach - (d) with milk **Answer: (c)** β€” Food reduces absorption of drugs degraded in the stomach (penicillin G) but can increase it for poorly soluble drugs (griseofulvin). **Q25.** A 78-year-old on a proton pump inhibitor needs calcium supplementation. The better choice is - (a) calcium citrate, which absorbs well in a less acidic stomach - (b) calcium carbonate on an empty stomach - (c) no calcium at all - (d) calcium carbonate, which needs acid **Answer: (a)** β€” Raised gastric pH (age or PPIs) reduces calcium carbonate absorption; calcium citrate absorbs better. **Q26.** An elderly man with atrophic gastritis develops dyspepsia on enteric-coated aspirin. A likely reason is - (a) slower gastric emptying - (b) increased protein binding - (c) higher gastric pH causing early release of the enteric-coated tablet - (d) reduced first-pass metabolism **Answer: (c)** β€” Raised gastric pH can release enteric-coated forms early, increasing GI adverse effects. ### Active Recall From memory: list the four ways drugs cross membranes; explain how pH and pKa decide ionisation with an example; say where oral drugs are absorbed and what slows it; define bioavailability, AUC and first-pass metabolism; calculate a volume of distribution; and explain protein binding, redistribution and the blood-brain barrier.