Absorption is the process by which a drug moves from its site of administration into the systemic circulation. The fraction of an administered dose that reaches the systemic circulation in unchanged, pharmacologically active form is the bioavailability (F), a parameter that is route-dependent, drug-dependent, and patient-dependent. Understanding the determinants of absorption is essential for predicting and adjusting the clinical effect of any orally or parenterally administered drug.
Drug molecules cross biological membranes by several mechanisms. Passive transcellular diffusion, the dominant mechanism for most small-molecule drugs, follows Fick's law: molecules move down a concentration gradient across the lipid bilayer at a rate proportional to the concentration difference, the membrane surface area, the lipid-water partition coefficient, and inversely proportional to membrane thickness. For a drug to diffuse readily by this mechanism it must be sufficiently lipophilic to partition into the membrane, and sufficiently small in molecular weight to traverse it. Carrier-mediated transport (facilitated diffusion and active transport) is important for drugs that structurally resemble endogenous substrates: methotrexate, for example, is transported into cells via the reduced folate carrier (RFC), and many drugs are substrates for intestinal efflux transporters such as P-glycoprotein (P-gp), which actively pump drug molecules back into the intestinal lumen and substantially reduce oral bioavailability. Paracellular diffusion through intercellular tight junctions is limited to small hydrophilic molecules and is generally a minor pathway for drugs.1
Ionization and the Henderson-Hasselbalch Equation. Most drugs are weak acids or weak bases, and their degree of ionization at physiological pH strongly influences their ability to cross biological membranes by passive diffusion. Only the un-ionized (neutral) form of a drug is sufficiently lipophilic to diffuse freely across the lipid bilayer. The Henderson-Hasselbalch equation relates the ionization state to pH and the drug's acid dissociation constant (pKa): for a weak acid, pH = pKa + log([A-]/[HA]), where [A-] is the ionized conjugate base concentration and [HA] is the un-ionized acid concentration. For a weak base, the analogous expression is pH = pKa + log([B]/[BH+]). When pH equals pKa, half the drug is ionized and half is un-ionized. In the acidic stomach (pH 1-2), weak acids (e.g., aspirin, pKa ~3.5) are predominantly un-ionized and well absorbed, while weak bases (e.g., morphine, pKa ~8.0) are predominantly ionized and poorly absorbed. In the more alkaline small intestine (pH 5.5-7.5), both weak acids and weak bases can achieve meaningful absorption, and the large surface area of the small intestine makes it the primary site of oral drug absorption regardless of ionization state.12
Bioavailability and First-Pass Metabolism. Oral bioavailability is determined by three sequential barriers: the fraction absorbed from the gastrointestinal (GI) lumen into the enterocyte (F absorption), the fraction surviving intestinal wall metabolism (F gut), and the fraction surviving hepatic first-pass metabolism (F hepatic). The product of these three fractions gives the overall oral bioavailability: F = F absorption x F gut x F hepatic. First-pass metabolism (presystemic metabolism) is the biotransformation of drug by intestinal and hepatic enzymes before it reaches the systemic circulation. Drugs with high hepatic extraction ratios -- such as lidocaine, morphine, propranolol, and nitroglycerin -- undergo extensive first-pass metabolism when given orally, resulting in very low oral bioavailability despite complete absorption from the gut. This is why intravenous (IV) lidocaine is the appropriate route for antiarrhythmic use while oral lidocaine is impractical, and why sublingual nitroglycerin bypasses first-pass to deliver rapid therapeutic concentrations. The cytochrome P450 (CYP) isoform CYP3A4 (cytochrome P450 3A4), expressed abundantly in both intestinal enterocytes and hepatocytes, is responsible for the majority of intestinal and hepatic first-pass metabolism for many drugs.13
Factors Modifying Absorption. Gastric emptying rate is a major determinant of the rate of oral drug absorption: drugs primarily absorbed in the small intestine reach their absorption site faster when gastric emptying is rapid (fasting state, prokinetic agents) and more slowly when emptying is delayed (food, opioids, anticholinergic drugs). Food can increase, decrease, or leave unchanged the bioavailability of specific drugs depending on whether the drug requires solubilization in bile acids for absorption (fat-soluble vitamins and drugs such as griseofulvin are better absorbed with fatty meals), whether food reduces gastric acidity sufficiently to affect ionization-dependent dissolution, or whether specific dietary components form chelates or complexes that prevent absorption (tetracyclines chelated by calcium, iron, and antacids). Formulation factors including tablet disintegration time, particle size, and the use of enteric coatings or extended-release matrices are pharmaceutical determinants of absorption rate and extent that are engineered to achieve specific pharmacokinetic profiles.2
IV administration: F = 100% by definition. High first-pass drugs with low oral F: lidocaine (~3%), nitroglycerin (~1%), morphine (~25%), propranolol (~25%). High oral bioavailability drugs (F >80%): metronidazole, fluconazole, most fluoroquinolones, levothyroxine (when taken fasting). P-glycoprotein (P-gp) substrates with clinically important efflux-mediated low bioavailability: digoxin, cyclosporine, loperamide. P-gp inhibition by ritonavir increases bioavailability of co-administered P-gp substrates.
After entering the systemic circulation, a drug distributes between plasma and tissue compartments according to its physicochemical properties, plasma protein binding, and tissue binding characteristics. The volume of distribution is the central pharmacokinetic parameter that quantifies the apparent space into which a drug distributes, and its magnitude has direct clinical implications for dosing strategy and for the interpretation of drug plasma concentrations.
Volume of Distribution. The apparent volume of distribution (Vd) is defined as the volume of fluid that would be required to contain the total amount of drug in the body at the same concentration as that measured in plasma: Vd = total amount of drug in body / plasma drug concentration. Vd is not a real physiological volume but a mathematical construct that describes the extent of drug distribution. A Vd approximating plasma volume (approximately 3-5 L) indicates that the drug is largely confined to the vascular compartment, typically due to high molecular weight, high plasma protein binding, or high water solubility that limits membrane permeation (e.g., heparin, large molecular weight proteins). A Vd approximating total body water (approximately 40 L) suggests the drug distributes into body fluids but not extensively into tissues (e.g., aminoglycosides). A Vd substantially exceeding total body water indicates extensive tissue sequestration: chloroquine has a Vd of approximately 200-800 L/kg (reflecting accumulation in lysosomes), and amiodarone has a Vd of approximately 60 L/kg (reflecting accumulation in adipose and other tissues). Drugs with large Vd are not efficiently removed by hemodialysis because most drug is in tissues rather than plasma.13
Plasma Protein Binding. Most drugs bind reversibly to plasma proteins, primarily albumin (which binds weakly acidic and neutral drugs) and alpha-1-acid glycoprotein (which binds basic drugs). Only the unbound (free) fraction of drug is pharmacologically active, able to cross membranes, and available for metabolism and elimination. The clinical implications of protein binding become important in specific circumstances: when a drug has high protein binding (greater than 90%), a small change in binding fraction produces a large change in free drug concentration; acute-phase responses that increase alpha-1-acid glycoprotein (trauma, surgery, inflammation) reduce the free fraction of basic drugs such as lidocaine; hypoalbuminemia in cirrhosis, nephrotic syndrome, or malnutrition reduces binding of acidic drugs, increasing the free fraction of drugs like phenytoin and warfarin and potentially causing toxicity at normally safe total concentrations. For phenytoin specifically, the correct target is a free drug concentration of 1-2 mg/L, not the total concentration of 10-20 mg/L, in patients with hypoalbuminemia or renal failure where protein binding is reduced.23
Blood-Brain Barrier and Other Specialized Barriers. The blood-brain barrier (BBB) is formed by cerebral capillary endothelial cells connected by unusually tight junctions, supported by astrocyte end-feet and pericytes. Drug access to the central nervous system (CNS) depends on lipophilicity, molecular weight, plasma protein binding (only unbound drug can cross), and active efflux by P-glycoprotein (P-gp) and other transporters expressed on the luminal surface of the BBB. Highly lipophilic, small, un-ionized drugs with low protein binding achieve good CNS penetration (e.g., most general anesthetics, benzodiazepines, ethanol), while polar, large, or highly protein-bound drugs penetrate poorly (e.g., aminoglycosides, most penicillins without meningeal inflammation). Inflammation of the meninges disrupts BBB tight junctions, dramatically increasing CNS penetration of drugs that normally have restricted access -- a pharmacokinetic fact of direct clinical relevance to antibiotic selection and dosing in bacterial meningitis. The placental barrier is similarly permeable to lipophilic, low-molecular-weight, un-ionized, and unbound drugs, necessitating careful attention to fetal drug exposure for any drug used in pregnancy.1
Always interpret drug concentrations in context of protein binding status. In hypoalbuminemia (albumin <2.5 g/dL), total phenytoin concentration underestimates free drug exposure: apply the Winter-Tozer equation or measure free phenytoin directly. Warfarin is >99% protein-bound; displacement interactions can transiently increase free warfarin and bleeding risk even without pharmacokinetic changes. Highly protein-bound drugs with narrow therapeutic windows (phenytoin, warfarin, valproate) require the most vigilance for protein binding changes.
Drug metabolism converts lipophilic drugs into more polar, water-soluble metabolites that can be excreted renally or biliarily. Metabolic reactions are classically divided into Phase I (functionalization) and Phase II (conjugation) reactions. The cytochrome P450 (CYP) enzyme system accounts for the majority of Phase I drug metabolism and is the source of the most clinically significant drug-drug interactions in pharmacology.
Phase I Reactions. Phase I reactions introduce or expose a polar functional group on the drug molecule, typically through oxidation, reduction, or hydrolysis. Oxidation by the hepatic microsomal CYP system is quantitatively the most important Phase I pathway. The CYP system consists of a superfamily of heme-containing monooxygenases; in humans, the isoforms CYP3A4 (cytochrome P450 3A4), CYP2D6 (cytochrome P450 2D6), CYP2C9 (cytochrome P450 2C9), CYP2C19 (cytochrome P450 2C19), and CYP1A2 (cytochrome P450 1A2) account for the metabolism of the majority of marketed drugs. CYP3A4 is the most abundant hepatic CYP isoform and metabolizes approximately 50% of drugs in clinical use, including cyclosporine, tacrolimus, midazolam, most statins, and many antiretroviral agents. Phase I reactions do not necessarily produce inactive metabolites: prodrugs require Phase I activation to generate pharmacologically active forms (codeine to morphine via CYP2D6; clopidogrel to its active thiol metabolite via CYP2C19), and some metabolites retain or even exceed the potency of the parent compound.4
Phase II Reactions. Phase II conjugation reactions attach an endogenous polar molecule to the drug or its Phase I metabolite, producing a highly water-soluble conjugate that is usually pharmacologically inactive and readily excreted. The principal Phase II reactions are glucuronidation (catalyzed by uridine diphosphate glucuronosyltransferases (UGTs)), sulfation (by sulfotransferases (SULTs)), acetylation (by N-acetyltransferases (NATs)), glutathione conjugation, and methylation. Glucuronidation is the most important Phase II reaction for drugs; morphine undergoes glucuronidation to morphine-6-glucuronide (M6G), which retains potent opioid activity and accumulates in renal failure, contributing to prolonged sedation. N-acetylation shows clinically important genetic polymorphism: slow acetylators (genetically determined by NAT2 (N-acetyltransferase 2) variants, more common in certain populations) accumulate higher concentrations of isoniazid and hydralazine, increasing the risk of isoniazid-induced peripheral neuropathy and hydralazine-induced lupus respectively.3
CYP Inducers and Inhibitors. CYP enzyme activity can be increased by inducers or decreased by inhibitors, producing clinically important drug-drug interactions. Enzyme induction involves upregulation of CYP gene transcription (often via the pregnane X receptor (PXR)), which takes days to weeks to develop and resolve. Potent CYP3A4 inducers include rifampin, carbamazepine, phenytoin, phenobarbital, and St. John's wort; co-administration with CYP3A4 substrates can reduce plasma concentrations of those substrates dramatically -- rifampin reduces plasma cyclosporine concentrations by over 80%, risking transplant rejection, and reduces combined oral contraceptive efficacy. Enzyme inhibition can be competitive (reversible, immediate) or mechanism-based (irreversible "suicide" inhibition, prolonged). Potent CYP3A4 inhibitors include azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin), and protease inhibitors (ritonavir); grapefruit juice irreversibly inhibits intestinal CYP3A4 and can dramatically increase the bioavailability of CYP3A4 substrates taken orally. CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) impair tamoxifen activation and may reduce efficacy in breast cancer treatment, and convert CYP2D6 extensive metabolizers into functional poor metabolizers.4
CYP3A4 substrate + azole antifungal: expect 2-10x increase in substrate concentration. Cyclosporine + rifampin: lose ~80% of cyclosporine exposure -- do not co-administer without drastically increasing cyclosporine dose with intensive monitoring. Warfarin (CYP2C9) + fluconazole: significant INR elevation within days. Clopidogrel + omeprazole (CYP2C19 inhibitor): reduced active metabolite generation -- use pantoprazole instead. Codeine in CYP2D6 ultra-rapid metabolizers: life-threatening morphine toxicity. Statin + clarithromycin/itraconazole: myopathy risk due to elevated statin exposure.
Drug elimination removes drug from the body through renal excretion, biliary excretion, and other minor routes. The mathematical relationship between dose, clearance, and the resulting plasma concentration over time defines the pharmacokinetic framework that clinicians use to design rational dosing regimens, individualize therapy in renal and hepatic impairment, and predict the time to steady state.
Renal Elimination. The kidney eliminates drugs by three mechanisms: glomerular filtration, active tubular secretion, and tubular reabsorption. Glomerular filtration is a passive process that filters unbound drug at a rate proportional to the glomerular filtration rate (GFR), effectively measured clinically by creatinine clearance (CrCl). Protein-bound drug is not filtered. Active tubular secretion transports drug from peritubular capillaries into the tubular lumen via organic anion transporters (OATs) and organic cation transporters (OCTs); this process can exceed the capacity of glomerular filtration for some drugs (e.g., penicillins are primarily renally eliminated by tubular secretion rather than filtration, explaining the historically used probenecid co-administration to block secretion and prolong penicillin half-life). Tubular reabsorption of un-ionized drug from the tubular lumen back into the circulation reduces net renal elimination; urinary pH manipulation exploits this mechanism in poisoning management -- alkalinizing the urine with sodium bicarbonate traps ionized salicylate (a weak acid) in the tubular lumen and increases its renal elimination in aspirin overdose. Drugs that depend heavily on renal elimination require dose adjustment in renal impairment, typically based on CrCl calculated from serum creatinine using the Cockcroft-Gault equation or estimated GFR (eGFR) by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.15
First-Order and Zero-Order Kinetics. The mathematical order of elimination kinetics determines how drug concentration changes over time. In first-order kinetics, the rate of elimination is proportional to the drug concentration: a constant fraction (not constant amount) of drug is eliminated per unit time, producing an exponential decline in plasma concentration. Most drugs follow first-order kinetics at therapeutic concentrations, and this linearity means that doubling the dose doubles the steady-state concentration. In zero-order (saturation) kinetics, the elimination pathway is saturated and a constant amount (not fraction) of drug is eliminated per unit time regardless of concentration. Ethanol, phenytoin, and aspirin at high doses exhibit zero-order kinetics because their metabolizing enzymes are saturated at therapeutic or near-therapeutic concentrations. Zero-order kinetics have critical clinical implications: small dose increases can produce disproportionately large increases in plasma concentration, making these drugs particularly prone to toxicity when doses are increased. Phenytoin is the paradigmatic clinical example -- a dose increase from 300 to 350 mg/day may move a patient from subtherapeutic to toxic drug levels because the elimination pathway is already saturating.12
Half-Life, Clearance, and Steady State. The elimination half-life (t1/2) is the time required for the plasma drug concentration to fall by 50%. For a drug with first-order kinetics, t1/2 = 0.693 x Vd / CL (clearance), where CL is the total body clearance. This relationship reveals that half-life is determined by both how much drug distributes into tissues (Vd) and how efficiently the body eliminates drug (CL); a drug with a large Vd can have a long half-life even if it is rapidly cleared from plasma, simply because there is a large reservoir of drug in tissues that continuously equilibrates back to plasma. After repeated dosing, plasma drug concentration accumulates until a steady state is reached, at which the rate of drug input equals the rate of elimination. Regardless of dose or dosing interval, steady state is reached after approximately 4 to 5 half-lives. Similarly, after drug discontinuation, approximately 4 to 5 half-lives are required for drug to be essentially eliminated from the body (greater than 97% cleared after 5 half-lives). This rule has direct clinical applications: digoxin (t1/2 approximately 36-40 hours) reaches steady state only after approximately 7-8 days of daily dosing; amiodarone (t1/2 weeks to months) reaches steady state only after months of continuous dosing, justifying the use of loading doses to accelerate the approach to therapeutic concentrations.35
Absorption: passive diffusion of un-ionized lipophilic drug; first-pass metabolism reduces oral bioavailability of high-extraction drugs. Distribution: Vd quantifies tissue distribution; protein binding determines free (active) fraction; BBB restricts CNS entry of polar/large/P-gp substrate drugs. Metabolism: Phase I (CYP oxidation) then Phase II (conjugation); CYP3A4 metabolizes ~50% of drugs; inducers (rifampin) decrease and inhibitors (azoles) increase substrate concentrations. Elimination: renal (GFR + tubular secretion); dose-adjust for CrCl in renal impairment. Kinetics: first-order = constant fraction eliminated; zero-order = constant amount (phenytoin, ethanol). Steady state reached in 4-5 half-lives regardless of dose or interval.
Ritter JM, Flower R, Henderson G, Loke YK, MacEwan D, Rang HP. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2019. ISBN 9780702074486.
ISBN 9780702074486Shargel L, Wu-Pong S, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics. 7th ed. New York: McGraw-Hill; 2016. ISBN 9780071830935.
ISBN 9780071830935Atkinson AJ Jr, Huang SM, Lertora JJL, Markey SP, eds. Principles of Clinical Pharmacology. 3rd ed. London: Academic Press; 2012. ISBN 9780123854711.
ISBN 9780123854711Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-141.
doi:10.1016/j.pharmthera.2012.12.007Rowland M, Tozer TN. Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. ISBN 9780781750097.
ISBN 9780781750097