Pharmacokinetics — ADME

Pharmacokinetics describes the movement of drugs through the body, encompassing absorption, distribution, metabolism, and excretion (ADME)—processes that determine drug concentration at the site of action over time. Understanding ADME is essential for predicting drug efficacy, avoiding toxicity, individualizing dosing, and managing drug-drug interactions. These principles apply universally across all therapeutic classes and are critical for clinical decision-making, from initial dosing to therapeutic drug monitoring. The interplay of ADME processes explains why patients with similar doses achieve different serum concentrations and clinical responses, necessitating dose adjustments in specific populations such as the elderly, those with renal/hepatic disease, and pregnant women. Mastery of ADME principles is foundational for USMLE Step 2 CK and essential for safe prescribing throughout clinical practice.

Pharmacokinetics is governed by predictable physical, chemical, and biological principles that determine how much drug reaches the systemic circulation, where it distributes, how it is eliminated, and the time course of these processes. The four ADME pillars operate sequentially and in parallel to establish the drug concentration-time profile, which directly determines pharmacological effect through the concentration-response relationship.

Absorption depends on the drug's physicochemical properties (lipophilicity, ionization, molecular weight), the route of administration, and local conditions at the absorption site. For orally administered drugs, absorption occurs primarily through the small intestine via passive diffusion (most common), active transport, or carrier-mediated mechanisms. The rate of absorption is characterized by the absorption rate constant (Ka), determining whether peak drug levels are achieved rapidly (high Ka) or gradually (low Ka). First-pass metabolism (also called presystemic metabolism) occurs when drugs absorbed from the GI tract enter the hepatic portal circulation before reaching systemic circulation, resulting in substantial metabolism before the drug reaches the bloodstream—this is why some drugs (nitroglycerin, isosorbide dinitrate) are given sublingually to bypass hepatic degradation. The bioavailability (F) represents the fraction of administered drug that reaches systemic circulation unchanged; intravenous administration achieves 100% bioavailability by definition, whereas oral bioavailability varies (e.g., warfarin ~100%, propranolol ~25% due to first-pass metabolism). For non-oral routes, absorption rates vary: intramuscular and subcutaneous injections provide slower, sustained absorption; transdermal patches bypass first-pass metabolism and provide steady-state levels; and inhalation achieves rapid absorption through the large respiratory surface area.

Distribution is determined by the volume of distribution (Vd), a theoretical compartment representing the apparent space into which a drug disperses; Vd = Dose / C₀, where C₀ is the initial plasma concentration. A small Vd (0.1 L/kg) indicates the drug remains primarily in the vascular space (e.g., heparin, highly protein-bound drugs), whereas a large Vd (>1 L/kg) suggests extensive tissue distribution (e.g., digoxin, lipophilic drugs accumulating in fat). Distribution is governed by: (1) protein binding—drugs binding extensively to plasma proteins (>90%, as with warfarin at 99%) have limited free (active) concentration and reduced interstitial penetration, but decreased protein binding in renal failure or liver disease increases free drug and toxicity risk; (2) lipophilicity—lipophilic drugs cross the blood-brain barrier and distribute to fat reserves, while hydrophilic drugs are restricted to the extracellular compartment; (3) tissue affinity—some drugs preferentially accumulate in specific tissues (digoxin in skeletal muscle, doxorubicin in tumors, chloroquine in liver); and (4) pH partitioning—weak acids accumulate in alkaline environments, weak bases in acidic compartments. The blood-brain barrier (tight junctions with efflux transporters like P-glycoprotein) restricts hydrophilic and highly protein-bound drugs, explaining why many antibiotics require very high doses or intrathecal administration to achieve therapeutic CNS concentrations.

Metabolism (biotransformation) converts drugs into metabolites that are typically more hydrophilic and readily excreted. Phase I reactions (oxidation, reduction, hydrolysis) are catalyzed primarily by the hepatic cytochrome P450 (CYP) system, particularly CYP3A4 (metabolizes ~50% of all drugs), CYP2D6, CYP2C9, and CYP1A2; these reactions expose or create functional groups for further modification. Phase II reactions (conjugation: glucuronidation, sulfation, acetylation, methylation) add hydrophilic moieties, dramatically increasing water solubility and promoting renal excretion. Phase III transporters actively pump drugs out of hepatocytes or renal tubules, regulating elimination. Hepatic metabolism is the primary route of elimination for lipophilic drugs; hepatic clearance depends on hepatic blood flow and the hepatic extraction ratio (ER)—high-ER drugs (propranolol, morphine) are flow-limited and sensitive to changes in liver blood flow, while low-ER drugs (warfarin, theophylline) depend on enzyme activity and are less affected by blood flow changes. Genetic polymorphisms in CYP450 enzymes create phenotypes: poor metabolizers (PMs) lack functional enzyme, accumulate drug, and risk toxicity; extensive metabolizers (EMs) are normal; ultra-rapid metabolizers (UMs) require higher doses for efficacy. CYP2D6 PMs (5-10% of Caucasians) cannot efficiently metabolize codeine, tramadol, and tricyclic antidepressants, necessitating dose adjustments or alternative agents. Drug-drug interactions at the cytochrome P450 level are frequent: enzyme inducers (phenytoin, rifampicin, carbamazepine, St. John's Wort) increase metabolism, reducing levels of coadministered drugs; enzyme inhibitors (ketoconazole, ritonavir, clarithromycin, grapefruit juice) decrease metabolism, elevating levels and toxicity risk. Extrahepatic metabolism occurs in the lungs (procainamide), kidneys, GI mucosa, and blood (ester drugs metabolized by pseudocholinesterase); in severe liver disease, extrahepatic sites may partially compensate.

Renal excretion is the predominant elimination route for hydrophilic drugs and accounts for 20-90% of total elimination for most agents. Renal clearance (CLr) comprises three mechanisms: (1) glomerular filtration of unbound drug (limited by molecular weight and charge); (2) active secretion via renal tubular transporters (organic anion and cation transporters) in the proximal tubule, which actively transport drugs into the urine (penicillins, probenecid, cimetidine); and (3) passive reabsorption along the concentration gradient in the distal tubule, particularly for lipophilic, non-ionized drugs. Creatinine clearance (eGFR) estimates glomerular filtration and guides dosing adjustments; at eGFR <30 mL/min, dose reductions are typically needed for renally cleared drugs, and at eGFR <10 mL/min, many drugs require substantial modification or are contraindicated. Biliary excretion eliminates large molecular weight compounds (>300 Da) and actively transported substrates; drugs entering the bile undergo enterohepatic circulation if not metabolized by colonic bacteria, prolonging their half-life. Pulmonary excretion is significant for volatile agents (volatile anesthetics, ethanol); skin excretion is minor except for some topical preparations. Non-renal clearance (hepatic + biliary + other) becomes critical in renal failure; some renally cleared drugs (enalapril → enalaprilat, levodopa → carbidopa) accumulate despite normal liver function.

Clearance (CL) represents the volume of plasma from which drug is irreversibly removed per unit time (mL/min or L/h); it is independent of dose or concentration and is the most important pharmacokinetic parameter for steady-state dosing. Total clearance = hepatic clearance + renal clearance + other. The elimination rate constant (ke) describes the fraction of body drug pool eliminated per unit time; ke = CL / Vd. Half-life (t½) is the time required for plasma concentration to decrease by 50%; t½ = 0.693 / ke = 0.693 × Vd / CL. Half-life determines the time to steady-state (approximately 5 half-lives, where 97% of steady-state is achieved), the dosing interval, and accumulation with repeated dosing. Steady-state is reached when drug input equals drug elimination, and the plasma concentration plateaus; steady-state concentration (Css) = (F × Dose) / (CL × τ), where τ is the dosing interval. For loading-dose calculations: Loading Dose = Vd × Target Concentration / F; this achieves therapeutic levels immediately, essential for drugs with long half-lives or serious conditions. Maintenance Dose = CL × Css × τ / F maintains steady-state levels.

Most drugs exhibit linear (first-order) pharmacokinetics, where elimination rate is proportional to drug concentration; clearance remains constant regardless of dose, and doubling the dose doubles the Css. However, nonlinear (zero-order) pharmacokinetics occurs when elimination pathways are saturated: elimination rate becomes independent of concentration, clearance decreases with higher doses, and small dose increases cause disproportionate increases in Css and toxicity risk. Phenytoin, salicylates, and ethanol at therapeutic/intoxicating concentrations exhibit zero-order kinetics; phenytoin's nonlinearity is particularly important because small dose increases near therapeutic levels can cause dramatic Css increases and toxicity. Michaelis-Menten kinetics describes this saturable elimination; as concentration approaches Km (the substrate concentration at half-maximal velocity), the system transitions from linear to zero-order behavior.

Alterations in ADME occur through intrinsic patient factors, extrinsic drug interactions, and disease states. Understanding these allows prediction and prevention of altered pharmacokinetics and toxicity.

Liver disease reduces metabolic capacity through hepatocyte loss (cirrhosis, acute hepatitis) or portal-systemic shunting (portosystemic collaterals), decreasing hepatic extraction and increasing systemic exposure. Acute liver injury can acutely impair enzyme activity; cirrhosis reduces both Phase I and Phase II metabolism, increases first-pass shunting via collaterals, and alters protein synthesis (reducing protein binding capacity). Drugs dependent on hepatic metabolism (warfarin, theophylline, phenytoin) accumulate, requiring dose reduction. Child-Pugh score and Model for End-Stage Liver Disease (MELD) help stratify hepatic function and guide dosing. High-extraction drugs (propranolol, morphine) are particularly sensitive to altered hepatic blood flow in cirrhosis.

Progressive renal failure from any cause (chronic kidney disease, acute kidney injury, diabetic nephropathy, glomerulonephritis) reduces eGFR, impairing glomerular filtration and active secretion. eGFR <60 mL/min/1.73m² (CKD stage 3 or higher) necessitates drug dose adjustments; eGFR <30 mL/min requires major reductions or alternative agents for renally cleared drugs. Certain drugs are nephrotoxic (aminoglycosides, contrast agents, NSAIDs, ACE inhibitors in specific settings), accelerating renal decline. Uremia (elevated BUN/creatinine) impairs urinary excretion through reduced GFR and can alter protein binding of acidic drugs.

Elderly patients (>65 years) experience reduced renal function (eGFR declines ~1 mL/min/year after age 40, often without creatinine elevation due to reduced muscle mass), decreased hepatic mass and blood flow, reduced body water (increased Vd for hydrophilic drugs, decreased for lipophilic drugs), and increased adipose tissue (Vd increases for lipophilic drugs, prolonging half-life). These changes cause drug accumulation, increased sensitivity, and toxicity risk; polypharmacy in elderly patients further elevates drug-drug interaction risk. Neonates and infants have immature Phase I and II metabolism, reduced renal function (GFR ~10% of adult values), higher body water (larger Vd for hydrophilic drugs), reduced protein binding (lower albumin), and increased blood-brain barrier permeability; sulfonamides are contraindicated in neonates (displacement of bilirubin from albumin causes kernicterus), and gray baby syndrome occurs with excessive chloramphenicol due to immature glucuronidation.

CYP2D6 deficiency affects ~7-10% of Caucasians (higher in Asians and Africans with different variants), causing poor metabolism of codeine, tramadol, venlafaxine, and many antipsychotics. CYP2C9 variants (particularly *2 and *3 alleles) reduce warfarin metabolism, requiring lower doses to prevent bleeding. CYP2C19 variants impair clopidogrel's activation to active metabolite, reducing antiplatelet efficacy (particularly important for stent thrombosis prevention); this is FDA black-box warning territory. N-acetyltransferase (NAT) polymorphisms determine acetylator phenotype: slow acetylators (higher in Caucasians) accumulate isoniazid, procainamide, and dapsone, risking toxicity; rapid acetylators may require higher doses. Thiopurine methyltransferase (TPMT) deficiency (0.3% of population) causes severe bone marrow toxicity with standard 6-mercaptopurine or azathioprine doses; TPMT genotyping is recommended before thiopurine therapy. Glucose-6-phosphate dehydrogenase (G6PD) deficiency causes hemolytic anemia with oxidative stress drugs (sulfonamides, antimalarials, nitrofurantoin, dapsone, rasburicase).

Enzyme inducers increase metabolism of coadministered drugs, reducing their Css and efficacy: rifampicin (induces CYP3A4, CYP2C9, CYP2C19) reduces warfarin levels, requiring INR monitoring and dose increase; carbamazepine and phenytoin induce multiple enzymes and cause breakthrough bleeding in oral contraceptive users; phenobarbital induces broad enzyme families; St. John's Wort induces CYP3A4, reducing warfarin and oral contraceptive efficacy. Enzyme inhibitors increase metabolism, elevating Css and toxicity risk: ketoconazole and other azole antifungals inhibit CYP3A4, elevating levels of statins (myopathy risk), calcineurin inhibitors, and many others; ritonavir (potent CYP3A4 inhibitor) dramatically raises levels of many antiretrovirals and is used therapeutically as a booster; clarithromycin (not azithromycin) inhibits CYP3A4; grapefruit juice irreversibly inhibits CYP3A4 in the gut, elevating levels of felodipine, simvastatin, and other drugs; SSRIs variably inhibit CYP450 (fluoxetine and paroxetine are significant inhibitors). Transporter inhibitors (P-glycoprotein, OATP) alter distribution and elimination; verapamil and quinidine inhibit renal secretion of digoxin, causing toxicity.