Pharmacokinetics describes the movement of drugs through the body over time, encompassing four major processes: absorption, distribution, metabolism, and excretion (ADME). Understanding pharmacokinetics is essential for determining appropriate dosing regimens, predicting drug concentrations, managing drug interactions, and individualizing therapy.
Drug Absorption
Absorption is the movement of a drug from the site of administration into the systemic circulation. The rate and extent of absorption determine onset of action and peak concentration.
Mechanisms of Absorption
Passive diffusion is the most common mechanism — drugs move down their concentration gradient through the lipid bilayer. Lipophilic drugs and unionized forms of weak acids/bases diffuse more readily. Facilitated diffusion uses carrier proteins to move drugs down their concentration gradient without energy expenditure. Active transport uses energy (ATP) to move drugs against concentration gradients, mediated by transporters such as P-glycoprotein and organic anion transporting polypeptides. Endocytosis involves the cell membrane engulfing large drug molecules.
Factors Affecting Absorption
Lipophilicity strongly influences absorption — more lipophilic drugs (propranolol, fentanyl) cross membranes easily. Molecular weight under 500 Da facilitates absorption. The degree of ionization depends on the drug’s pKa and the pH of the environment — unionized forms are more lipophilic and absorb better (the pH-partition hypothesis). Gastric pH ranges from 1-2 (stomach) to 6-8 (ileum), affecting which drugs are ionized at each site. Blood flow to the absorption site determines how quickly dissolved drug is carried away (maintaining a concentration gradient). Gastrointestinal surface area is enormous (200 m² in the small intestine), making it the primary site of drug absorption for oral drugs. Gastric emptying rate delays or accelerates drug delivery to the small intestine — food, opioids, and anticholinergics slow gastric emptying; metoclopramide accelerates it.
Bioavailability
Bioavailability (F) is the fraction of the administered dose that reaches the systemic circulation unchanged. For intravenous administration, bioavailability is 100% by definition. For oral administration, bioavailability is reduced by incomplete absorption and first-pass metabolism (metabolism in the gut wall and liver before the drug reaches systemic circulation). Drugs with high first-pass metabolism include propranolol, lidocaine, nitroglycerin, and morphine. Sublingual, buccal, and rectal routes bypass first-pass metabolism to varying degrees.
Distribution
Distribution is the reversible movement of a drug between compartments (blood, tissues, organs). The volume of distribution (Vd) relates the amount of drug in the body to its plasma concentration. A low Vd (3-5 L) indicates the drug is confined to the plasma compartment (heparin, warfarin). A moderate Vd (12-20 L) indicates distribution to extracellular fluid (aminoglycosides, lithium). A Vd of 25-40 L indicates distribution throughout total body water (ethanol, theophylline). A Vd greater than 40 L indicates extensive tissue binding or sequestration (digoxin Vd ~500 L, chloroquine Vd ~13,000 L).
Protein Binding
Many drugs bind reversibly to plasma proteins, primarily albumin (for acidic drugs) and alpha-1-acid glycoprotein (for basic drugs). Only unbound (free) drug is pharmacologically active. Highly protein-bound drugs (over 90% bound) include warfarin (99%), phenytoin (90%), and NSAIDs. In conditions with low albumin (liver disease, nephrotic syndrome, malnutrition), free drug levels increase, raising the risk of toxicity. Protein binding displacement interactions occur when one drug displaces another from binding sites, transiently increasing the free concentration of the displaced drug.
Metabolism
Drug metabolism (biotransformation) converts lipid-soluble drugs into water-soluble metabolites that can be excreted. It occurs primarily in the liver but also in the gut wall, kidneys, lungs, and plasma.
Phase I Reactions
Phase I reactions introduce or expose a functional group through oxidation, reduction, or hydrolysis. The cytochrome P450 (CYP) enzyme family is the most important Phase I system. Major CYP isoforms include CYP3A4 (metabolizes 50% of all drugs), CYP2D6 (20-25%), CYP2C9 (15%), CYP2C19 (10%), and CYP1A2 (5%). Genetic polymorphisms in CYP enzymes produce significant inter-individual variability in drug metabolism. CYP2D6 poor metabolizers (7-10% of Caucasians) have reduced clearance of many antidepressants, antipsychotics, opioids, and beta-blockers. CYP2C19 poor metabolizers (2-5% of Caucasians, 15-20% of Asians) have reduced clearance of proton pump inhibitors and clopidogrel.
Phase II Reactions
Phase II reactions conjugate the drug or Phase I metabolite with endogenous molecules (glucuronic acid, sulfate, glutathione, glycine, or methyl groups) through enzymes such as UDP-glucuronosyltransferases (UGTs), sulfotransferases, and glutathione S-transferases. Phase II metabolites are generally inactive and water-soluble.
First-Pass Metabolism
Orally administered drugs absorbed from the GI tract travel via the portal vein to the liver before reaching systemic circulation. If the drug is extensively metabolized in the liver (or gut wall), a substantial fraction is eliminated before reaching systemic circulation. Drugs with high first-pass metabolism include propranolol, lidocaine, nitroglycerin, verapamil, and morphine. Strategies to bypass first-pass metabolism include sublingual, buccal, transdermal, and intravenous routes.
Excretion
Excretion is the irreversible removal of drug from the body, primarily by the kidneys. Renal excretion involves three processes: glomerular filtration (passive, depends on protein binding — only free drug is filtered), tubular secretion (active transport, can be saturated and competitively inhibited, important for drug-drug interactions involving anionic and cationic transport systems), and tubular reabsorption (passive diffusion back into blood, influenced by urine pH and drug pKa — ionized drugs are trapped in urine and excreted).
Elimination Half-Life
Half-life (t½) is the time required for the drug concentration to decrease by 50%. Half-life determines the time to reach steady state (4-5 half-lives for accumulation), the dosing interval (typically every half-life for repeated dosing), and the duration of drug effect after discontinuation. Clearance (CL) is the volume of plasma from which drug is completely removed per unit time. CL and Vd determine half-life: t½ = 0.693 × Vd / CL.
Therapeutic Drug Monitoring
Some drugs require monitoring of serum concentrations to optimize efficacy and minimize toxicity — narrow therapeutic index drugs (digoxin, warfarin, lithium, theophylline, aminoglycosides, vancomycin, cyclosporine, tacrolimus, carbamazepine, valproate, phenytoin). TDM guides dose adjustments, assesses adherence, and identifies drug interactions or metabolic abnormalities.
Summary
Pharmacokinetics (ADME) determines drug concentration at the site of action over time. Absorption depends on drug properties (lipophilicity, pKa, molecular weight) and formulation. Distribution depends on perfusion, protein binding, and tissue affinity. Metabolism (Phase I CYP450, Phase II conjugation) converts drugs to water-soluble metabolites and is the source of many drug interactions and genetic variability. Excretion is primarily renal. Half-life and clearance guide dosing intervals. TDM is essential for drugs with narrow therapeutic indices.