Step 1 · Pharmacology Principles

Pharmacokinetics: ADME

Name: Pharmacokinetics: ADME
Creator: Veli Bakalov, MD

What the body does to the drug: absorption, distribution, metabolism, excretion

Pharmacology Principles·Pharmacokinetics·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Bioavailability (F) is the fraction reaching systemic circulation unchanged: IV = 1; oral F is lowered by incomplete absorption and hepatic first-pass metabolism, which sublingual, transdermal, and IV routes bypass.
Vd = amount in body / plasma concentration: low Vd = large, charged, or protein-bound drugs held in plasma; high Vd = lipophilic, tissue-bound drugs.
Clearance = rate of elimination / Cp = Vd × ke; it falls in renal or hepatic failure.
Half-life = 0.693 × Vd / CL: it rises when Vd increases or clearance falls (halving CL doubles t1/2).
Steady state takes 4–5 half-lives (94% at 4, 97% at 5) regardless of dose or frequency; elimination after stopping takes the same time.
Loading dose = Cp × Vd / F and is unchanged in organ failure; maintenance dose = Cp × CL × τ / F and must be reduced in renal or hepatic failure.
First-order kinetics eliminates a constant fraction per unit time (constant half-life, most drugs); zero-order eliminates a constant amount because enzymes are saturated.
Zero-order drugs (PEA: phenytoin, ethanol, high-dose aspirin) show disproportionate level rises with small dose increases; phenytoin toxicity progresses from nystagmus to ataxia.
Urine alkalinization with bicarbonate traps weak acids (aspirin, phenobarbital) in ionized form and speeds excretion; ammonium chloride does the same for weak bases (amphetamines).

Absorption and bioavailability

Pharmacokinetics vs pharmacodynamics. Pharmacokinetics (PK) is what the body does to a drug: Absorption, Distribution, Metabolism, and Excretion (ADME). Pharmacodynamics is what the drug does to the body. PK sets the concentration-time profile that drives the drug's effect.

Bioavailability (F). The fraction of an administered dose that reaches the systemic circulation unchanged. IV drug has F = 1 (100%) by definition. Oral F is lower because of incomplete absorption and first-pass metabolism, so F is used to scale oral doses (oral dose = IV-equivalent dose / F).

First-pass effect. Drug absorbed from the gut travels through the portal vein to the liver and is partly metabolized before it reaches the systemic circulation. Drugs with high first-pass metabolism need much larger oral than IV doses. Routes that avoid it: IV, sublingual (nitroglycerin acts fast because it skips hepatic first pass), transdermal, inhaled, and partly rectal.

Crossing membranes. Most drugs are absorbed by passive diffusion of the nonionized, lipid-soluble form. How much of a weak acid or base is nonionized depends on its pKa relative to local pH (Henderson-Hasselbalch): weak acids are nonionized in acidic surroundings, weak bases in alkaline ones.

Distribution: volume of distribution

Vd. V_d = amount of drug in the body / plasma concentration (C_p). It is an apparent volume, a proportionality constant rather than a real space, and it can far exceed total body water when a drug is sequestered in tissue.

Interpreting volume of distribution

Vd	Where the drug stays	Drug properties	Example
Low (~3 L, near the plasma volume)	Plasma	Large, charged, or highly plasma protein-bound	Heparin
Medium	Extracellular fluid	Small, hydrophilic	Aminoglycosides
High	Tissues, including fat	Small, lipophilic, tissue-bound	Amiodarone

Protein binding. Only free (unbound) drug distributes, acts, and is filtered. Hypoalbuminemia (liver disease, nephrotic syndrome) raises the free fraction of highly protein-bound drugs and increases their Vd.

Metabolism, clearance, and half-life

Hepatic metabolism. Makes lipophilic drugs polar enough to excrete. Phase I (oxidation, reduction, hydrolysis, largely by cytochrome P450) gives slightly polar metabolites that may remain active; phase II (glucuronidation, acetylation, sulfation) gives very polar, usually inactive conjugates for renal excretion. Elderly patients lose phase I capacity first.

Renal excretion. Free drug is filtered at the glomerulus and some is actively secreted by the proximal tubule, while nonionized drug can be passively reabsorbed. Ion trapping exploits this: alkalinizing the urine with bicarbonate keeps weak acids (aspirin, phenobarbital) ionized and speeds their excretion; acidifying the urine (ammonium chloride) does the same for weak bases (amphetamines).

Clearance (CL). The volume of plasma cleared of drug per unit time: CL = rate of elimination / C_p = V_d × k_e, where k_e is the elimination rate constant. Total clearance is the sum of renal, hepatic, and other routes, and it falls in renal or hepatic failure, mandating lower maintenance doses.

Half-life. The time for concentration to fall by 50% under first-order kinetics: t_1/2 = 0.693 × V_d / CL = 0.693 / k_e (0.693 = ln 2). Half-life rises when Vd increases or clearance falls; halving clearance with Vd unchanged doubles it. Half-life alone sets both the time to steady state and the time to eliminate a drug.

F = 1Bioavailability of an IV dose

4–5 t_1/2Time to steady state, or to eliminate a stopped drug

94% / 97%Fraction of steady state reached at 4 / 5 half-lives

Steady state and dosing

Steady state. With regular dosing or a constant infusion, concentration climbs until rate in = rate out. That takes 4–5 half-lives regardless of dose size or frequency: the dose sets the level reached, not the time to reach it (a drug with a 24-hour half-life needs about 4–5 days).

1 half-life50% of steady state
2 half-lives75%
3 half-lives87.5%
4–5 half-lives94–97% = steady state

Approach to steady state

Loading dose. Loading dose = target C_p × V_d / F. It fills the volume of distribution so the therapeutic level is reached at once, skipping the 4–5 half-life wait. Because it depends on Vd and not clearance, it is unchanged in renal or hepatic failure. Worked example: target 10 mg/L, Vd 50 L, oral F 0.5 → 10 × 50 / 0.5 = 1,000 mg.

Maintenance dose. Replaces what is eliminated. Dosing rate = target C_p × CL / F; dose per interval = C_p × CL × τ / F, where τ is the dosing interval. Because it tracks clearance, it must be reduced in renal or hepatic failure (smaller doses or longer intervals) to avoid accumulation and toxicity.

Loading vs maintenance dose

Feature	Loading dose	Maintenance dose
Formula	C_p × V_d / F	C_p × CL × τ / F
Depends on	Volume of distribution	Clearance
Purpose	Fill the compartment quickly	Replace ongoing elimination
Renal or hepatic failure	Unchanged	Reduced

First-order vs zero-order kinetics

First-order (linear) kinetics. A constant fraction of drug is eliminated per unit time, so the elimination rate is proportional to concentration. Most drugs behave this way, giving a constant half-life independent of dose; a plot of ln(C_p) vs time is a straight line.

Zero-order kinetics. A constant amount is eliminated per unit time because the metabolizing enzymes are saturated, so the rate is independent of concentration and there is no fixed half-life. Classic examples (PEA; a pea is round like a zero): Phenytoin (high dose), Ethanol, and Aspirin (high dose).

Dangerous nonlinearity. Once enzymes saturate, a small dose increase produces a disproportionate rise in plasma level and a prolonged effective half-life. Phenytoin shows it best: a modest dose change can push levels into toxicity, with nystagmus and then ataxia. Therapeutic drug monitoring guides dosing of these narrow-window agents.

First-order vs zero-order elimination

Feature	First-order	Zero-order
Eliminated per unit time	Constant fraction	Constant amount
Rate vs concentration	Proportional	Independent (enzymes saturated)
Half-life	Constant	Not constant; lengthens as level rises
Linear plot	ln(C_p) vs time	C_p vs time
Dose increase	Proportional rise in level	Disproportionate rise; toxicity
Examples	Most drugs	Phenytoin, ethanol, aspirin (high doses)