Introduction to Medical Pharmacology
Physicochemical determinants, routes of administration, first-pass metabolism, and oral absorption kinetics
Chapter 2 · Module 1 of 5 · PKIN-01Section 1
Lipophilicity, ionization, and the properties that allow drugs to cross biological membranes
Before a drug can reach its target, it must cross one or more biological membranes. The physical and chemical properties of a drug molecule determine whether it can do this efficiently, which route of administration is appropriate, and how much of the administered dose will ultimately reach the systemic circulation.
The dominant mechanism of drug absorption is passive transcellular diffusion: drug molecules dissolve through the lipid bilayer of cell membranes, move across the cell interior, and exit through the basolateral membrane into the bloodstream. No energy is required and no transporter protein is involved. The driving force is the concentration gradient from the site of administration to the plasma.
For passive transcellular diffusion to occur efficiently, a drug needs to be sufficiently lipophilic to dissolve into the membrane's lipid core. Lipophilicity is measured by the partition coefficient between octanol and water (log P), with an optimal range of approximately 1 to 3. Drugs that are too hydrophilic cannot enter the lipid bilayer; drugs that are too lipophilic become trapped within the membrane and cannot exit on the other side. Molecular weight is the second major determinant: molecules larger than approximately 500 daltons cannot diffuse through cell membranes at clinically useful rates, which is why large biologics such as insulin and monoclonal antibodies cannot be given orally.
The Lipinski Rule of Five codifies these empirical observations as a screening tool in drug development. A candidate drug is predicted to have poor oral absorption if it violates two or more of these criteria: molecular weight above 500 daltons, log P above 5, more than 5 hydrogen bond donors, or more than 10 hydrogen bond acceptors. Most orally absorbed drugs satisfy these criteria, which is why they remain useful benchmarks even though exceptions exist.
Most drugs are weak acids or weak bases, meaning they exist in both ionized and un-ionized forms in aqueous solution. Only the un-ionized form is lipophilic enough to cross membranes by passive diffusion; the ionized form is water-soluble and membrane-impermeant. The fraction of drug in the un-ionized form at any location in the body is determined by the drug's acid dissociation constant (pKa) and the local pH, as described by the Henderson-Hasselbalch relationship.
This pH partition effect has direct clinical consequences. A weak acid drug (such as aspirin, pKa approximately 3.5) is mostly un-ionized in the acidic stomach (pH 1 to 2) and substantially ionized in the basic small intestinal fluid (pH 6 to 7). Despite this, most oral drug absorption occurs in the small intestine rather than the stomach, because the enormous surface area of the small intestinal mucosa — estimated at approximately 200 square meters when microvilli are included — far outweighs the pH disadvantage. A weak base (such as many antidepressants and antipsychotics, pKa 8 to 10) is largely ionized in the stomach and un-ionized in the small intestine, making the small intestine the favored absorption site for basic drugs regardless of their pKa.
A smaller fraction of drug absorption occurs through the aqueous channels between adjacent intestinal epithelial cells — paracellular diffusion. This pathway is accessible only to very small, hydrophilic molecules because the tight junctions between cells restrict passage to molecules below approximately 200 daltons. Most drugs are too large for meaningful paracellular absorption.
Active transport proteins at the intestinal brush border complicate the picture in two directions. Some drugs are taken up by influx transporters that carry them from the intestinal lumen into the epithelial cell, enhancing absorption beyond what passive diffusion alone would achieve. More clinically relevant are efflux transporters, which actively pump drug molecules back out of the epithelial cell into the intestinal lumen, reducing effective absorption. P-glycoprotein, encoded by the multidrug resistance-1 gene, is the most clinically important intestinal efflux transporter. Digoxin, several antiretroviral drugs, and many other agents are substrates for intestinal P-glycoprotein. Drugs that inhibit P-glycoprotein (including certain antifungals, cyclosporine, and amiodarone) can substantially increase the absorption of co-administered P-glycoprotein substrates — a mechanism underlying several clinically important drug interactions.
Determinants of Oral Absorption — At a Glance
Lipophilicity (log P 1–3 optimal): required for passive membrane crossing. Molecular weight below 500 daltons: required for membrane permeability. Ionization: un-ionized fraction crosses membranes; ionized fraction does not. Small intestine dominates oral absorption regardless of pH, due to surface area advantage. P-glycoprotein efflux at brush border reduces absorption of substrates including digoxin; inhibition by other drugs increases exposure.
Section 2
How the route of delivery shapes onset, bioavailability, and clinical selection
The route of administration is one of the most consequential decisions in pharmacotherapy. It determines whether first-pass metabolism is encountered, how rapidly a therapeutic concentration can be achieved, and whether delivery is even feasible for a given drug or patient situation.
Oral administration is the most commonly used route because it is safe, convenient, and does not require a trained provider. After swallowing, a drug must dissolve in gastrointestinal fluid, survive the gastric environment, cross the intestinal epithelium, and pass through the portal circulation to the liver before reaching the systemic circulation. The time from ingestion to first detectable plasma levels is typically 15 to 60 minutes for immediate-release formulations, though this varies with gastric emptying rate, food intake, and the drug's physicochemical properties.
The oral route is not appropriate for drugs destroyed by gastric acid or intestinal enzymes (insulin, heparin, most peptide biologics), for patients who cannot swallow or absorb reliably, or when a rapid and predictable concentration rise is required (status epilepticus, anaphylaxis, cardiac arrest).
Administration under the tongue (sublingual) or against the inner cheek (buccal) delivers drug through the highly vascular oral mucosa directly into the systemic venous circulation, entirely bypassing hepatic first-pass metabolism. This makes these routes pharmacologically valuable for drugs that would be substantially eliminated during oral first-pass transit.
Nitroglycerin is the paradigmatic example: its oral bioavailability is essentially zero because near-complete hepatic extraction eliminates the absorbed dose before it reaches the systemic circulation. Sublingual administration produces effective plasma concentrations within one to two minutes. Buprenorphine achieves approximately 30 to 50 percent sublingual bioavailability versus roughly 10 percent oral bioavailability, making the sublingual route essential for opioid use disorder treatment. Fentanyl buccal film exploits the same principle for rapid onset analgesia in breakthrough cancer pain.
The transdermal route delivers drug through the skin into the systemic circulation, bypassing the gastrointestinal tract and hepatic first-pass metabolism. Only lipophilic, low-molecular-weight drugs can penetrate the stratum corneum at clinically useful rates. Commercially available transdermal systems include nicotine, fentanyl, buprenorphine, scopolamine, estradiol, testosterone, clonidine, and rotigotine patches.
The advantages of transdermal delivery are sustained and controlled drug release over 24 to 72 hours or longer, reduced peak-to-trough fluctuation compared to oral dosing, avoidance of first-pass metabolism, and elimination of gastrointestinal absorption variability. The limitation is the slow onset: it takes 12 to 24 hours or longer to reach steady-state plasma concentrations through most transdermal systems, which must be anticipated when initiating treatment.
Intramuscular and subcutaneous injections deposit drug into tissue compartments from which absorption occurs by diffusion across the capillary endothelium into the systemic circulation. Both routes bypass the gastrointestinal tract and hepatic first-pass metabolism. Intramuscular injection into well-perfused muscle produces faster absorption (typically 10 to 30 minutes for aqueous solutions) than subcutaneous injection, because muscle has higher capillary density and blood flow than subcutaneous adipose tissue.
Subcutaneous administration is used for insulin, low-molecular-weight heparins, and many biologics such as adalimumab and etanercept, where slow sustained absorption is appropriate. Depot formulations in oil or as sparingly soluble salts exploit the intramuscular or subcutaneous compartment as a slow-release reservoir: haloperidol decanoate, paliperidone palmitate, leuprolide acetate depot, and medroxyprogesterone acetate injectable suspension are important clinical examples that provide weeks to months of drug delivery from a single injection.
Intravenous administration delivers drug directly into the systemic circulation, achieving 100 percent bioavailability by definition. There is no absorption step, no first-pass metabolism, and onset of pharmacological effect begins within one circulation time. The intravenous route is the route of choice when a rapid and predictable plasma concentration is required, when oral absorption is unreliable or impossible, or when the drug cannot be given by other routes.
Intravenous bolus injection produces the highest immediate peak concentration; intravenous infusion allows controlled titration of plasma concentration over time. The intravenous route carries unique risks: line infection, phlebitis, air embolism, and the impossibility of dose retrieval if an adverse reaction occurs immediately after administration. For drugs with concentration-dependent toxicity, the rate of intravenous administration matters as much as the total dose.
First-Pass Bypassed
Routes avoiding hepatic first-pass
First-Pass Encountered
Routes subject to hepatic first-pass
Section 3
Presystemic elimination, high-extraction drugs, and clinical consequences for dosing
First-pass metabolism, also called presystemic elimination, is the biotransformation of an orally administered drug before it reaches the systemic circulation. It is one of the most clinically important determinants of oral drug bioavailability and explains why the oral dose of many drugs must be dramatically higher than the equivalent parenteral dose to achieve the same systemic drug exposure.
After absorption across the intestinal epithelium, drug molecules enter the portal venous circulation and are delivered directly to the liver before reaching the systemic venous circulation. The liver expresses high concentrations of cytochrome P450 enzymes — predominantly cytochrome P450 3A4, cytochrome P450 2C9, cytochrome P450 2D6, and others — that metabolize drugs as they pass through the hepatic sinusoids. Drugs with high affinity for these enzymes undergo substantial biotransformation during this first hepatic transit, and only the fraction that escapes metabolism emerges into the systemic circulation to produce pharmacological effects.
The degree of hepatic first-pass extraction is described by the hepatic extraction ratio, which represents the fraction of drug removed from the portal blood during a single hepatic pass. Drugs with a hepatic extraction ratio above approximately 0.7 are classified as high-extraction drugs, meaning the liver removes more than 70 percent of the absorbed dose on first pass. These drugs typically have oral bioavailability well below 30 percent.
Understanding which drugs are subject to extensive first-pass metabolism is clinically essential for route selection and dose conversion. Morphine has an oral bioavailability of approximately 30 percent due to hepatic glucuronidation on first pass; the intravenous and subcutaneous routes are therefore preferred for reliable analgesia in acute settings, and the oral-to-intravenous dose conversion ratio reflects this difference. Nitroglycerin has essentially zero oral bioavailability because of near-complete hepatic extraction, which is why it must be given sublingually, transdermally, or intravenously. Lidocaine is a high-extraction drug with essentially zero oral bioavailability that must be given intravenously for antiarrhythmic use. Propranolol has an oral bioavailability of approximately 25 to 35 percent, and its high inter-patient variability in first-pass extraction is one reason plasma levels vary several-fold between individuals at the same oral dose.
The liver is not the only site of presystemic drug elimination. The intestinal epithelium itself expresses significant concentrations of cytochrome P450 3A4, which can metabolize drug molecules within the enterocyte before they even enter the portal circulation. For drugs that are substrates for intestinal cytochrome P450 3A4, a substantial fraction of the absorbed dose may be metabolized in the intestinal wall, compounding the hepatic first-pass loss and further reducing overall oral bioavailability. The relative contributions of intestinal and hepatic first-pass metabolism vary among individuals and contribute to the wide inter-patient differences in oral bioavailability seen with cytochrome P450 3A4 substrates such as cyclosporine, tacrolimus, and several calcium channel blockers.
Grapefruit juice irreversibly inhibits intestinal cytochrome P450 3A4 through furanocoumarins that form covalent adducts with the enzyme, destroying its catalytic activity. Because the effect is irreversible at the molecular level, new enzyme must be synthesized to restore activity, and a single glass of grapefruit juice can inhibit intestinal cytochrome P450 3A4 for 24 to 72 hours. The consequence is substantially increased oral bioavailability of drugs that normally undergo significant intestinal first-pass metabolism by cytochrome P450 3A4, sometimes increasing plasma exposures by several-fold.
Drugs with clinically significant grapefruit juice interactions include simvastatin and lovastatin (up to 15-fold area under the curve increase in some reports), felodipine, nifedipine, cyclosporine, tacrolimus, and buspirone. These interactions can cause toxicity even when the drug is taken at a standard dose. The interaction is specific to intestinal cytochrome P450 3A4: grapefruit juice does not substantially inhibit hepatic cytochrome P450 3A4 at normal consumption volumes, so the magnitude of interaction is greatest for drugs with high intestinal first-pass extraction.
Liver disease alters first-pass metabolism through two distinct mechanisms. Portosystemic shunting in cirrhosis — where blood bypasses the liver sinusoids through collateral vessels — physically prevents hepatic extraction even when enzyme activity is preserved, increasing oral bioavailability of high-extraction drugs and requiring dose reduction. Hepatocellular disease additionally reduces enzyme expression, further impairing first-pass metabolism.
Enzyme inducers and inhibitors dramatically alter first-pass metabolism. Rifampin (an antibiotic used to treat tuberculosis) induces intestinal and hepatic cytochrome P450 3A4 and cytochrome P450 2C9, markedly reducing the bioavailability of many co-administered drugs. Azole antifungals such as ketoconazole and itraconazole inhibit intestinal and hepatic cytochrome P450 3A4, increasing the bioavailability of sensitive substrates and requiring dose reduction to avoid toxicity. These interactions must be anticipated proactively when managing patients on multiple drugs.
High-Extraction Drugs — Clinical Anchors
Nitroglycerin: essentially zero oral bioavailability; sublingual, transdermal, or intravenous only. Morphine: oral bioavailability approximately 30 percent; intravenous or subcutaneous preferred for acute analgesia. Lidocaine: intravenous only for antiarrhythmic use. Propranolol: 25–35 percent oral bioavailability with high inter-patient variability. Grapefruit juice: inhibits intestinal cytochrome P450 3A4 irreversibly for 24–72 hours; avoid with simvastatin, lovastatin, cyclosporine, tacrolimus, and other sensitive substrates. Cirrhosis: increases oral bioavailability of high-extraction drugs via portosystemic shunting; reduce oral doses accordingly.
Section 4
Absolute and relative bioavailability, dose equivalency between routes, and generic substitution
Bioavailability is the pharmacokinetic parameter that quantifies how much of an administered dose reaches the systemic circulation in an unchanged, active form. It is the conceptual bridge between the dose written on the prescription and the actual drug exposure the patient experiences.
Absolute bioavailability, designated by the letter F, is the fraction of an administered dose that reaches the systemic circulation as unchanged drug, expressed as a decimal between 0 and 1, or equivalently as a percentage. It is measured by comparing the total drug exposure after non-intravenous administration to the total drug exposure after intravenous administration of the same dose, using the area under the plasma concentration-time curve as the measure of total exposure. The intravenous route serves as the reference standard because intravenous administration achieves 100 percent bioavailability by definition.
An F value of 0.30 means that 30 percent of the oral dose reaches the systemic circulation; the remaining 70 percent is lost to incomplete absorption, first-pass metabolism, or both. These two causes of low bioavailability are pharmacologically distinct: incomplete absorption means the drug never entered the portal circulation, while first-pass extraction means the drug was absorbed but eliminated before reaching systemic circulation. Both reduce F, but they respond differently to interventions.
The practical consequence of bioavailability is that the oral dose required to achieve the same systemic drug exposure as an intravenous dose is higher by the factor of 1 divided by F. If a drug has F equal to 0.25 and the effective intravenous dose is 10 milligrams, the equivalent oral dose is 10 divided by 0.25, equaling 40 milligrams. This relationship underlies oral-to-intravenous and intravenous-to-oral dose conversion decisions and explains why oral doses often appear disproportionately large compared to parenteral doses.
This conversion is particularly consequential when transitioning between routes. Converting a patient from intravenous morphine to oral morphine requires applying the oral bioavailability factor (approximately 0.30 for single doses) to avoid under-dosing or over-dosing. When transitioning from oral to intravenous, the dose must be reduced proportionally or serious toxicity can result. These conversions are explicitly calculated in clinical practice using drug-specific equianalgesic tables that implicitly incorporate average population bioavailability values.
Relative bioavailability compares the drug exposure from one formulation to another without using intravenous administration as the reference. It is the metric used in generic drug approval. The United States Food and Drug Administration requires that a generic drug demonstrate bioequivalence to the innovator reference drug: the 90 percent confidence interval for the ratio of the generic product's area under the curve and maximum plasma concentration to those of the reference must fall within the acceptance range of 80 to 125 percent.
For most drugs, this range of acceptable variation is clinically inconsequential, and generic substitution is safe and appropriate. However, for drugs with a narrow therapeutic index — drugs where the difference between a therapeutic and a toxic plasma concentration is small — even the permitted 20 to 25 percent variation in exposure can be clinically important. Phenytoin, cyclosporine, tacrolimus, warfarin, levothyroxine, and lithium are the most commonly cited examples. When a patient stabilized on one brand or formulation of a narrow therapeutic index drug is switched to another, therapeutic drug monitoring is warranted to confirm that drug concentrations remain within the therapeutic range.
Gastric pH profoundly affects the bioavailability of drugs that require an acidic gastric environment for dissolution and absorption. Ketoconazole, itraconazole capsules, atazanavir, and posaconazole oral suspension all depend on gastric acid for adequate dissolution. Proton pump inhibitor co-administration — commonly prescribed for acid reflux or gastroprotection — markedly reduces plasma concentrations of these drugs and can result in treatment failure for fungal infections or inadequate antiretroviral exposure.
Food intake at the time of drug administration can either increase or decrease bioavailability. For most drugs, food delays but does not reduce the extent of absorption; taking a drug with food slows gastric emptying and delays peak concentration but the total amount absorbed is similar. For some lipophilic drugs, however, food substantially increases absorption because co-ingested dietary fat enhances dissolution and gastrointestinal solubilization. Posaconazole delayed-release tablets, griseofulvin, and ivermectin must be taken with food for adequate absorption; package labeling specifies this requirement, and failure to eat before dosing results in subtherapeutic plasma concentrations.
Surgically altered gastrointestinal anatomy can markedly reduce bioavailability for a range of drugs. Patients who have undergone Roux-en-Y gastric bypass surgery have altered gastric pH, reduced surface area for absorption in bypassed segments, and accelerated gastrointestinal transit. Levothyroxine, mycophenolate mofetil, and oral anticoagulants may require higher doses or alternative formulations after bariatric surgery, and these patients should be monitored more closely after dose initiation or change.
Bioavailability Alterations Requiring Clinical Action
Proton pump inhibitor plus ketoconazole, itraconazole, atazanavir, or posaconazole: reduced absorption, potential treatment failure — administer with acidic beverage or switch formulation. Food requirement: posaconazole, griseofulvin, ivermectin must be taken with food for adequate absorption — check labeling. Roux-en-Y gastric bypass: levothyroxine, mycophenolate mofetil, and oral anticoagulants may need higher doses — monitor levels. Narrow therapeutic index drugs after generic switch: measure drug levels before assuming stable dosing.
Section 5
Peak concentration, time to peak, and total exposure — the three parameters that describe the plasma concentration-time profile
When a drug is administered orally, the resulting plasma concentration-time profile reflects the simultaneous processes of absorption into and elimination from the systemic circulation. Three parameters summarize this profile and carry direct clinical information about the adequacy of dosing, the likelihood of efficacy, and the risk of toxicity.
The maximum (peak) plasma concentration is reached when the rate of absorption from the gastrointestinal tract equals the rate of elimination from plasma. After this point, absorption slows and then ceases while elimination continues, and the plasma concentration falls. Cmax is clinically relevant because many drug toxicities are concentration-dependent at the peak: a high Cmax may push the plasma concentration above the toxic threshold even if the average concentration over the dosing interval is well within the therapeutic window.
Phenytoin is a clear example: central nervous system toxicity manifesting as nystagmus, ataxia, and cognitive impairment correlates with peak concentrations. Extended-release formulations of phenytoin reduce Cmax, which is the pharmacokinetic rationale for their use in patients experiencing concentration-dependent side effects with immediate-release dosing. The goal of extended-release formulations for most drugs is to reduce Cmax while preserving the total drug exposure as measured by the area under the curve.
The time to peak concentration indicates how rapidly a drug acts after oral administration and is particularly relevant for drugs used for acute symptom relief. A shorter Tmax means faster onset of effect, which is the pharmacokinetic goal for analgesics, hypnotics, and acute migraine treatments.
Formulation design directly targets Tmax. Liquid-filled soft gelatin capsule formulations of ibuprofen reach Tmax in approximately 35 minutes compared to 90 to 120 minutes for standard tablets. Sumatriptan nasal spray and subcutaneous injection reach Tmax within 20 minutes compared to 90 to 120 minutes for oral tablets, which is meaningful for treating an established migraine attack. Conversely, extended-release formulations deliberately increase Tmax to smooth the concentration-time profile and reduce adverse effects associated with rapid concentration rises: extended-release niacin reduces flushing, extended-release metformin reduces gastrointestinal symptoms, and modified-release opioids reduce the peak intensity of central nervous system and respiratory effects.
The area under the plasma concentration-time curve from time zero to infinity represents the total systemic drug exposure and is proportional to the total amount of drug that entered the systemic circulation. When clearance is constant — as in linear pharmacokinetics — doubling the dose doubles the area under the curve proportionally. The area under the curve is the primary metric for bioequivalence assessment: two formulations are bioequivalent if their areas under the curve fall within the 80 to 125 percent acceptance range, meaning the total drug exposures are comparable even if the shapes of the concentration-time curves differ slightly.
An extended-release formulation of a drug ideally preserves the same area under the curve as the immediate-release formulation given at the same total daily dose, while reducing the Cmax and increasing the Tmax. When this is achieved, total drug exposure and efficacy are maintained while peak-related toxicity is reduced and dosing frequency can be decreased.
Food intake at the time of dosing alters all three kinetic parameters through multiple mechanisms: slowing gastric emptying (delaying Tmax and sometimes reducing Cmax for drugs absorbed proximally), providing co-solubilizing lipids, stimulating bile flow, and changing gastric pH. For most drugs, food delays Tmax without substantially altering the area under the curve, which is clinically acceptable for chronic therapies but undesirable for acute-use drugs where a delayed onset of effect matters.
For drugs requiring rapid onset (acute analgesics, hypnotics, acute migraine treatments), taking the drug on an empty stomach speeds absorption and is generally recommended. For drugs where food substantially increases total absorption (posaconazole, griseofulvin, ivermectin), taking the drug with a fatty meal is required for adequate exposure, and this instruction must be communicated clearly to patients.
Cmax, Tmax, and AUC — Comparison Across Formulations
Immediate-release: highest Cmax, shortest Tmax, greatest peak-to-trough fluctuation, most frequent dosing, fastest onset. Extended-release: lower Cmax, later Tmax, reduced fluctuation, less frequent dosing, AUC preserved. Enteric coating: delayed Tmax (1–4 hours), onset unsuitable for acute pain. Food: delays Tmax for most drugs (acceptable for chronic use); increases total exposure for posaconazole, griseofulvin, ivermectin (must be taken with food).
Section 6
Immediate-release, extended-release, enteric coating, and prodrug strategies
Drug formulation is not merely a pharmaceutical convenience. It is a pharmacokinetic tool that can profoundly alter the absorption profile of an active drug, shaping its onset, duration, peak exposure, and suitability for a given clinical indication. Clinicians who understand the pharmacokinetic consequences of formulation choices can select the right formulation for the right situation and anticipate the consequences of inadvertent or intentional substitution.
Immediate-release formulations are designed to release the active drug rapidly, typically within 30 minutes of ingestion. They produce the fastest onset of action, the highest Cmax, and the earliest Tmax among oral dosage forms. These characteristics make immediate-release formulations appropriate when rapid onset is clinically required or when short duration of action enables dose titration.
The clinical tradeoff is the greatest peak-to-trough fluctuation in plasma concentration over the dosing interval: the concentration rises sharply after each dose and falls substantially before the next. For drugs with concentration-dependent adverse effects at the peak — immediate-release nifedipine causing reflex tachycardia, immediate-release opioids causing rapid peak sedation — extended-release formulations are often preferable.
Extended-release formulations engineer slow drug release over an extended period, typically 8 to 24 hours, through matrix systems, membrane-controlled reservoir systems, or osmotic pump technology. The pharmacokinetic consequences are lower Cmax, later Tmax, and reduced peak-to-trough fluctuation, with total area under the curve preserved if the drug is completely released and absorbed. Extended-release formulations allow less frequent dosing (once-daily instead of three or four times daily), which can improve adherence for chronic therapy.
A critically important safety rule applies to all extended-release formulations: they must never be crushed, chewed, or broken. Destroying the release-controlling mechanism causes immediate release of the entire dose, called dose dumping, which is equivalent to receiving multiple immediate-release doses simultaneously. Dose dumping with extended-release opioids has caused fatal respiratory depression. This is the pharmacokinetic rationale for abuse-deterrent formulations that use polymer matrices designed to become viscous when manipulated, preventing extraction or crushing.
Enteric-coated formulations use a polymer coating that remains intact in the acidic gastric environment but dissolves at the near-neutral pH of the duodenum and proximal small intestine. Enteric coating serves two distinct pharmacological purposes, and understanding which purpose applies to a specific drug clarifies the clinical use.
The first purpose is protecting acid-labile drugs from gastric degradation. Proton pump inhibitors such as omeprazole are irreversibly inactivated by gastric acid and must be enteric-coated to survive passage through the stomach intact. The second purpose is protecting the gastric mucosa from drugs that cause direct mucosal irritation when released in an acidic environment. Enteric-coated aspirin releases the drug in the small intestine rather than the stomach, reducing the local mucosal injury that occurs with uncoated aspirin. This does not eliminate aspirin's systemic effects on prostaglandin synthesis and is therefore not a reliable strategy for preventing aspirin's gastrointestinal bleeding complications.
The pharmacokinetic consequence of enteric coating is delayed absorption: the drug passes through the stomach unabsorbed and absorption begins only when the tablet reaches the duodenum, typically 1 to 4 hours after ingestion depending on gastric emptying rate and food intake. Enteric-coated aspirin is therefore appropriate for once-daily antiplatelet prophylaxis but a poor choice for the management of acute pain where rapid onset is required.
A prodrug is a pharmacologically inactive compound that undergoes biotransformation in the body to release the active drug. Prodrug design is used when the active drug has physicochemical properties that prevent adequate oral absorption, when tissue-targeted delivery is needed, or when direct administration of the active form causes mucosal toxicity.
Valacyclovir is the most instructive example for second-year pharmacology: it is the valine ester prodrug of acyclovir, designed to exploit intestinal amino acid transporter-mediated uptake. After absorption, valacyclovir is cleaved by intestinal and hepatic esterases to release acyclovir. The result is approximately 55 percent oral bioavailability for valacyclovir-derived acyclovir compared to approximately 15 to 20 percent for acyclovir itself. This formulation difference is clinically significant: the higher bioavailability of valacyclovir allows less frequent dosing with higher systemic acyclovir exposures than is achievable with oral acyclovir at any practical dose.
Immediate-Release
Fastest onset, highest peak
Extended-Release
Smoothed profile, less frequent dosing
Enteric Coating
Delayed absorption, protected drug or mucosa
Prodrug
Inactive precursor activated after absorption
| Author / Organization | Title | Source |
|---|---|---|
| Rowland M, Tozer TN | Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, 4th ed. | Lippincott Williams & Wilkins, 2011 |
| Shargel L, Wu-Pong S, Yu ABC | Applied Biopharmaceutics and Pharmacokinetics, 7th ed. | McGraw-Hill, 2016 |
| Lipinski CA et al. | Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings | Adv Drug Deliv Rev. 2001;46(1-3):3-26 |
| Giacomini KM et al. | Membrane transporters in drug development | Nat Rev Drug Discov. 2010;9(3):215-236 |
| Brunton LL, Hilal-Dandan R, Knollmann BC, eds. | Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. | McGraw-Hill, 2018 |
| Wilkinson GR | Drug metabolism and variability among patients in drug response | N Engl J Med. 2005;352(21):2211-2221 |
| Bailey DG, Dresser G, Arnold JM | Grapefruit-medication interactions: forbidden fruit or avoidable consequences? | CMAJ. 2013;185(4):309-316 |
| Dressman JB, Reppas C | In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs | Eur J Pharm Sci. 2000;11(Suppl 2):S73-S80 |