Pharmacokinetics: Drug Distribution, Elimination, and Biotransformation

Comprehensive practice flashcards covering drug distribution, renal and non-renal elimination, pharmacokinetics, and hepatic biotransformation pathways.

Drug Distribution

The reversible movement of a drug between body compartments, wherein the drug leaves the bloodstream and enters the interstitial and intracellular fluids and tissues to reach its site of action.

Free Drug

The unbound, pharmacologically active fraction of a drug circulating in plasma that is capable of crossing cell membranes, producing a clinical response, and undergoing glomerular filtration and hepatic metabolism.

Apparent Volume of Distribution ($V_d$)

A proportionality constant relating the total amount of drug in the body to its concentration measured in plasma ($V_d = \frac{\text{Dose administered i.v.}}{\text{Plasma concentration}}$), reflecting the extent to which a drug distributes into extravascular tissues versus remaining in the bloodstream.

Total Body Water (TBW) Fluid Compartments

The physiological fluid distribution in an average $70\,\text{kg}$ adult, consisting of $42\,\text{L}$ total body water divided into intracellular fluid ($28\,\text{L}$) and extracellular fluid ($14\,\text{L}$, comprising $3\,\text{L}$ plasma, $10.5\,\text{L}$ interstitial fluid, and $0.5\,\text{L}$ transcellular fluid).

Central Compartment

The pharmacokinetic compartment comprising blood and highly perfused organs (heart, brain, lungs, liver, and kidneys) with which a drug rapidly equilibrates following administration.

Peripheral Compartment

The pharmacokinetic compartment comprising less-perfused tissues and organs (adipose tissue, skeletal muscle, bone, and skin) where drug uptake and equilibration occur more slowly.

Redistribution

The process whereby a highly lipid-soluble drug (such as thiopental) rapidly equilibrates with well-perfused organs like the brain to produce an immediate effect, and subsequently moves out into poorly perfused reservoir tissues (such as muscle and fat), terminating its central action.

Blood-Brain Barrier (BBB)

A continuous anatomical barrier created by brain capillary endothelial cells with tight junctions and perivascular astrocyte foot processes (glial feet) that permits entry of lipid-soluble, hydrophobic drugs while restricting polar, hydrophilic, or ionized drugs.

Fetal Ion Trapping

A phenomenon wherein weak bases cross the placenta into the more acidic fetal circulation ($\text{pH } 7.0\text{--}7.2$ compared to maternal $\text{pH } 7.4$), become protonated and ionized, and are unable to diffuse back across lipid membranes into maternal plasma.

Alpha-1-Acid Glycoprotein (Orosomucoid)

A plasma protein that preferentially binds basic drugs; its concentration rises during acute inflammatory states, leading to increased binding and reduced free drug levels.

Displacement Interaction

A competitive drug-drug interaction in which a drug with higher affinity for plasma protein binding sites displaces another drug with lower affinity, causing an abrupt rise in the free concentration of the displaced agent (e.g., indomethacin displacing warfarin).

Loading Dose ($LD$)

An initial dose administered to rapidly fill the volume of distribution and achieve a therapeutic steady-state plasma concentration ($C_{ss}$) in an acute setting, calculated as $LD = V_d \times C_{ss}$.

Drug Excretion

The irreversible transfer of unchanged drugs and their metabolites from the internal body fluids to the external environment, primarily mediated by renal excretion, along with non-renal routes such as bile, lungs, sweat, and feces.

Glomerular Filtration (GF)

A unidirectional, non-selective renal process driven by capillary hydrostatic pressure that filters free, unbound drugs through the glomerulus into the tubular lumen while excluding cellular elements and large, protein-bound macromolecules.

Active Tubular Secretion

A carrier-mediated, energy-dependent, capacity-limited transport process in proximal renal tubules that secretes drugs from peritubular capillaries into the tubular lumen regardless of plasma protein binding.

Organic Anion and Cation Transporters (OAT & OCT)

Families of carrier proteins in the renal tubule that actively secrete organic acids/anions (e.g., penicillins, salicylates, glucuronides) and organic bases/cations (e.g., morphine, catecholamines), respectively.

Probenecid Interaction

The pharmacological use of probenecid to competitively inhibit the organic anion transporter (OAT), blocking the tubular secretion of penicillins and cephalosporins to prolong their duration of action.

Passive Tubular Reabsorption

The passive back-diffusion of uncharged, lipophilic drug molecules from the concentrated renal tubular fluid across tubular membranes into peritubular capillaries, modulated by urine $\text{pH}$ and drug $\text{p}K_a$.

Urinary Alkalinization

A therapeutic strategy involving intravenous sodium bicarbonate administration to raise urine $\text{pH}$ to $\ge 8.0$, which ionizes weak acids like salicylic acid (aspirin) to prevent tubular reabsorption and accelerate renal elimination up to $18\text{ times}$ the normal rate.

Clearance ($CL$)

A pharmacokinetic measure representing the volume of plasma completely cleared of a drug per unit of time, calculated as $CL = \frac{\text{Rate of elimination}}{\text{Plasma concentration}}$.

Total Body Clearance ($CL_{\text{total}}$)

The overall systemic clearance of a drug representing the sum of clearances from all individual eliminating organs: $CL_{\text{total}} = CL_{\text{hepatic}} + CL_{\text{renal}} + CL_{\text{pulmonary}} + CL_{\text{other}}$.

First-Order Elimination Kinetics

A process in which a constant fraction of drug is eliminated per unit of time, causing plasma drug concentration to decrease exponentially over time with a constant elimination half-life ($t_{1/2}$).

Zero-Order Elimination Kinetics (Saturation Kinetics)

A process occurring when clearance pathways are saturated, wherein a constant amount of drug is eliminated per unit of time regardless of plasma concentration, resulting in a linear decline, a concentration-dependent half-life, and disproportionate accumulation at higher doses.

Elimination Half-Life ($t_{1/2}$)

The time required for the plasma drug concentration to decrease by $50\%$, mathematically defined for first-order elimination as $t_{1/2} = \frac{0.693 \times V_d}{CL}$.

Steady-State Concentration ($C_{ss}$)

The plateau state during regular dosing or continuous IV infusion where the rate of drug input equals the rate of drug elimination, typically achieved after $4\text{ to }5\text{ half-lives}$.

Biotransformation

The chemical conversion of a drug by enzymatic systems within a living organism, primarily transforming lipophilic, unionized molecules into hydrophilic, ionized metabolites for excretion.

Prodrug

An inactive compound that undergoes in vivo biotransformation to release its active, therapeutically effective metabolite (e.g., levodopa to dopamine, prednisone to prednisolone, fosamprenavir to amprenavir).

Phase I Reactions (Functionalization)

Nonsynthetic enzymatic modifications (oxidation, reduction, hydrolysis, cyclization, decyclization) that unmask or introduce polar functional groups ($-\text{OH}$, $-\text{NH}_2$, $-\text{SH}$, $-\text{COOH}$) to generate active, inactive, or toxic metabolites.

Phase II Reactions (Conjugation)

Synthetic reactions wherein a drug or Phase I metabolite is coupled with an endogenous substrate (glucuronic acid, sulfate, acetate, glutathione, or amino acids) to yield a highly polar, water-soluble, and predominantly inactive metabolite.

Glucuronidation

The most common high-capacity Phase II reaction, mediated by microsomal UDP-glucuronosyltransferase (UGT) using UDP-glucuronic acid to attach an activated sugar to substrates such as morphine and acetaminophen.

Microsomal Enzymes

Enzymes located in the smooth endoplasmic reticulum of hepatocytes (including cytochrome P450, flavin monooxygenases, and glucuronyl transferase) that catalyze oxidation, reduction, hydrolysis, and glucuronide conjugation, and are subject to enzyme induction.

Non-Microsomal Enzymes

Enzymes found in the cytoplasm, mitochondria, or plasma (e.g., MAO, xanthine oxidase, alcohol dehydrogenase, esterases, and non-glucuronide transferases) that are non-inducible and often exhibit genetic polymorphism.

Cytochrome P450 (CYP) Enzymes

A superfamily of microsomal mixed-function oxidases primarily located in the liver and gastrointestinal tract that utilize molecular oxygen and reduced NADPH to perform oxidative biotransformation.

CYP3A4

The most abundant hepatic cytochrome P450 enzyme (accounting for approximately $30\%$ of liver CYPs and metabolizing approximately $50\%$ of prescribed drugs), which is inhibited by macrolides, azole antifungals, and grapefruit juice, and induced by rifampin and carbamazepine.

CYP2D6

A genetically polymorphic cytochrome P450 enzyme responsible for metabolizing antipsychotics, tricyclic antidepressants, and codeine, showing reduced activity or functional deficiency in approximately $10\%$ of Caucasian individuals.

Hofmann Elimination

A non-enzymatic spontaneous chemical degradation process in plasma and tissues that inactivates a drug without relying on hepatic metabolism or renal excretion, exemplified by the neuromuscular blocker atracurium.

Enzyme Induction

A process wherein repeated exposure to a drug or chemical stimulates the synthesis of microsomal enzymes, accelerating the metabolism of substrate drugs and potentially causing therapeutic failure or increased toxic metabolite generation.

Autoinduction

A phenomenon in which a drug induces its own hepatic microsomal metabolism over time, leading to accelerated clearance and requiring dose escalation to maintain therapeutic plasma concentrations (e.g., carbamazepine).

Enzyme Inhibition

A rapid process where a drug or substance reduces the activity of drug-metabolizing enzymes, slowing down the biotransformation of co-administered substrates and predisposing to drug accumulation and toxicity (e.g., cimetidine, erythromycin, ketoconazole).