Drug Clearance and Rate of Elimination | Pharmacokinetics Lecture 12

Renal elimination occurs through glomerular filtration and tubular secretion. Large molecules and protein-bound drugs cannot pass glomerular endothelium and require organic cation transporters in the proximal tubule. Lipid-soluble drugs can be reabsorbed and re-enter circulation. Hepatic elimination involves active secretion into bile canaliculi, transport to the intestine for fecal elimination, and potential reabsorption through the hepatic vein. Conjugated drugs with glucuronic acid can be modified by gut microbiota, removing the conjugate and allowing parent molecule reabsorption.

Elimination is drug removal from the body, primarily through renal excretion (urine) and hepatic/biliary excretion (feces). Renal excretion involves glomerular filtration (20% of drugs filtered, only free drug), tubular secretion (via OAT and OCT transporters), and tubular reabsorption (lipophilic drugs can be reabsorbed). Metabolism converts lipophilic drugs to hydrophilic metabolites more readily eliminated. Ionization affects elimination: ionized drugs cannot cross membranes. Changing urinary pH alters ionization (acidifying urine increases basic drug elimination). Enterohepatic circulation creates recycling pathways (e.g., ethinylestradiol, digoxin). Alternative routes include pulmonary excretion (anesthetics, alcohol) and breast milk excretion. Renal function significantly affects elimination, requiring dose adjustments in impairment.

Drug elimination is the final pharmacokinetic principle, following administration, absorption, distribution, and metabolism. The body eliminates drugs primarily through urinary elimination (the primary pathway for removing metabolic byproducts and toxic substances) and fecal elimination (removing undigested food residues). Hepatic metabolism transforms drugs into polar, water-soluble molecules to facilitate renal excretion. The nephron, with approximately one million units per kidney, forms urine through three processes: glomerular filtration (where 20% of cardiac output passes through capillaries and small molecules enter Bowman's capsule), tubular reabsorption (lipophilic drugs return to circulation), and tubular secretion (80% of drugs are added to filtrate using organic acid/base transporters). Drug elimination kinetics depend on solubility: hydrophilic drugs are eliminated through urine while lipophilic drugs are reabsorbed and recirculate. Both liver and kidney must function properly for effective elimination.

Drug metabolism (biotransformation) converts lipophilic drugs into hydrophilic forms for elimination. The liver is the primary organ, though kidneys, lungs, and intestines also contribute. Four outcomes exist: inactive to inactive metabolite (most common), active to active metabolite, inactive to active metabolite (prodrugs), and inactive to toxic metabolite (e.g., acetaminophen to NAPQI). Phase 1 reactions (oxidation, reduction, hydrolysis) modify drug structure, while Phase 2 reactions (conjugation with glucuronic acid) increase water solubility. Drugs are eliminated through three main routes: hepatic metabolism, biliary excretion (liver to bile to feces), and renal excretion. Renal elimination involves glomerular filtration (only free drugs filtered, GFR ~125 mL/min), active tubular secretion (via OAT/OCT transporters for charged drugs), and tubular reabsorption. Ion trapping occurs when drugs become ionized in urine and cannot be reabsorbed.

Drug elimination occurs primarily through renal excretion and hepatobiliary secretion. The kidneys eliminate drugs through glomerular filtration (approximately 10-20% of drugs filtered based on size and charge) and tubular secretion (active transport using OAT and OCT transporters). The nephron consists of glomerulus, proximal convoluted tubule (site of most secretion/reabsorption), loop of Henle, distal convoluted tubule, and collecting duct. Urinary pH significantly affects elimination through ion trapping: acidic drugs are more readily excreted in alkaline urine, while basic drugs are more readily excreted in acidic urine. Clinically, alkalinizing urine accelerates salicylate elimination in overdose. Beyond renal elimination, drugs are also eliminated via the hepatobiliary route, where conjugated metabolites enter bile and are secreted into the intestines. Intestinal flora can deconjugate these metabolites, potentially allowing reabsorption (enterohepatic recirculation). Additional elimination routes include sweat, tears, and breast milk, which is particularly important for pregnant and lactating women.

Zero-order: rate independent of concentration (R = k), [A] = [A]₀ - kt, t₁/₂ = [A]₀/(2k). First-order: rate proportional to concentration (R = k[A]), ln([A]₀/[A]) = kt, t₁/₂ = 0.693/k. Half-life is constant for first-order, proportional to initial concentration for zero-order. Pseudo-first-order occurs when one reactant is in large excess.

Zero-order reactions: Rate = k (independent of concentration), [A] = -kt + [A]_0, linear concentration-time plot with slope = -k. First-order reactions: Rate = k[A], ln([A]/[A]_0) = -kt, linear ln[A] vs. time plot with slope = -k. For H2O2 decomposition with k = 7.30 × 10^(-4) s^(-1) and [H2O2]_0 = 2.32 M, at t = 1200 s: [H2O2]_t = 0.967 M.

First-order kinetics means a constant fraction of drug is eliminated per unit time (e.g., 50% eliminated each half-life). Zero-order kinetics means a constant amount of drug is eliminated per unit time regardless of concentration. Alcohol elimination follows zero-order kinetics. In first-order kinetics, clearance capacity is high and not saturated, while in zero-order kinetics, clearance capacity is saturated. The graph of first-order kinetics shows exponential decline in plasma concentration, while zero-order kinetics shows linear decline.

Zero-order reactions have rate independent of concentration (Rate = k). Concentration-time graph is linear with negative slope. Half-life is proportional to initial concentration: t₁/₂ = [A]₀/(2k). First-order reactions have rate proportional to concentration (Rate = k[A]). Concentration-time graph is exponential decay. Half-life is independent of initial concentration: t₁/₂ = 0.693/k. The rate constant has units of time⁻¹ for first-order reactions.

This section provides a complete treatment of chemical kinetics, covering first-order and zero-order reactions. The definition of first-order reactions is given with the rate law expression Rate = k[A]^1. Examples include H2O2 and SO2Cl2 decomposition. The derivation of the first-order rate law is explained step-by-step: starting with -d[A]/dt = k[A], separating variables, integrating both sides, and applying limits to obtain ln([A]₀/[A]ₜ) = kt. The section also covers zero-order reactions and their rate law expressions. Students are advised to understand the derivation rather than rote memorization, as this is essential for long answer questions in board examinations.

The concentration-time profile shows how drug concentration in blood changes over time for different administration routes. Intravenous administration produces the highest initial concentration because the entire dose enters the bloodstream immediately. Sublingual administration produces rapid concentration rise due to direct venous absorption. Intramuscular injection produces rapid concentration rise from muscle tissue absorption. Subcutaneous injection produces slower concentration rise from subcutaneous tissue absorption. Oral administration produces the slowest concentration rise due to multiple barriers and first-pass metabolism.

Plasma concentration-time curves show distinct phases: absorption (drug enters circulation), distribution (rapid decline as drug moves to tissues), and elimination (slower decline as drug is metabolized and excreted). The distribution phase reflects drug's ability to leave blood and enter tissues. Equilibrium between compartments establishes before elimination dominates. Three-compartment models add adipose tissue for lipophilic drugs. Drugs accumulating in fat tissue (melatonin, cannabinoids) show very long terminal elimination phases lasting months or years.

The plasma concentration-time profile is a fundamental pharmacokinetic concept that plots drug concentration in plasma against time after administration. After drug administration, the drug undergoes disintegration and dissolution in the stomach, then absorbs through blood capillaries into systemic circulation. Blood samples are collected at regular intervals, centrifuged to separate serum, and analyzed to measure drug concentration. The resulting graph shows drug concentration initially increasing as absorption occurs, reaching a maximum (Cmax), then decreasing as elimination processes dominate. The profile consists of two phases: the absorption phase (left of Cmax) where absorption predominates, and the elimination phase (right of Cmax) where elimination becomes dominant. At Cmax, the rate of absorption equals the rate of elimination. Key parameters include Tmax (time to reach Cmax), AUC (total drug exposure), and the therapeutic window between minimum effective concentration (MEC) and maximum safe concentration (MSC).

Pharmacokinetics studies drug absorption (entry into bloodstream), distribution (movement throughout body), metabolism (chemical modification), and excretion (elimination). Key parameters include plasma concentration-time profiles showing drug concentration changes over time. The direct relationship between drug concentration and pharmacological effect forms the basis for therapeutic monitoring. Important parameters include: Peak Plasma Concentration (Cmax) - maximum drug concentration achieved; Time to Peak Concentration (Tmax) - time to reach Cmax; Area Under the Curve (AUC) - total drug exposure over time, expressed in mcg/mL×hours. These parameters assess drug bioavailability and guide therapeutic drug monitoring.

Pharmacology is the study of drugs' action on the body and the body's response to drugs, derived from Greek words meaning 'drop of poison' and 'study of knowledge.' It is divided into pharmacodynamics (what drugs do to the body) and pharmacokinetics (what the body does to drugs). Pharmacokinetics describes drug exposure through four key processes: Absorption (drug enters bloodstream), Distribution (drug spreads to tissues), Metabolism (chemical transformation), and Excretion (elimination from body). Key concentration-time profile parameters include Peak Concentration (Cmax), Time to Peak (Tmax), Minimum Effective Concentration (MEC), Minimum Toxic Concentration (MTC), Therapeutic Range, Onset of Action, and Duration of Action. IV administration bypasses absorption, requiring extreme caution to ensure sterility and absence of particulate matter.