How Medications Work in Your Body: Absorption, Distribution, Metabolism, and Excretion

The Pharmacokinetic Journey: ADME

Every medication follows a predictable path through the body. Understanding ADME (Absorption, Distribution, Metabolism, Excretion) explains why dosing, timing, food, and individual factors matter.

1. Absorption: Getting Into Blood

Route	Mechanism	Key Factors	Onset
Oral (PO)	GI tract → portal vein → liver (first-pass)	Formulation, food, pH, motility, surface area, transporters	15 min - 2 hr
Sublingual/Buccal	Oral mucosa → systemic (bypasses first-pass)	Lipophilicity, saliva, perfusion	Minutes
Transdermal	Skin layers → capillaries	Stratum corneum barrier, hydration, blood flow, patch tech	Hours-days
Inhalation	Alveoli → pulmonary veins	Particle size, breath hold, lung disease	Seconds-minutes
Injection (IV, IM, SC)	Direct (IV) or tissue depot (IM/SC)	Blood flow, formulation, injection technique	Immediate (IV) to hours (SC depot)
Rectal/Vaginal	Mucosal absorption	Partial first-pass bypass, variable absorption	Variable

2. Distribution: Getting to Target

Blood flow: High to brain, heart, liver, kidneys; low to fat, bone
Protein binding: Albumin, α1-acid glycoprotein. Only FREE drug is active. Displacement interactions possible.
Volume of distribution (Vd): Theoretical volume drug occupies. High Vd = tissue sequestration (lipophilic). Low Vd = plasma-confined.
Barriers: Blood-brain barrier (BBB), placental, blood-testis. Lipophilic, non-ionized, small molecules cross.

3. Metabolism: Chemical Transformation

Phase I (Functionalization): CYP450 enzymes (mainly liver). Oxidation, reduction, hydrolysis. Creates active/inactive/toxic metabolites.
Phase II (Conjugation): UGT, SULT, GST, NAT. Glucuronidation, sulfation, methylation. Increases water solubility.
Genetic polymorphism: CYP2D6 (PM/IM/EM/UM), CYP2C19, TPMT, DPYD → dose adjustments
Induction/Inhibition: Drug-drug, drug-food, drug-herb interactions. Major clinical significance.

4. Excretion: Leaving the Body

Renal: Glomerular filtration + tubular secretion - reabsorption. Requires water solubility. Dose adjust in CKD.
Biliary/Fecal: Large molecules, conjugates. Enterohepatic recirculation possible.
Pulmonary: Volatile anesthetics, alcohol
Other: Sweat, saliva, tears, breast milk (clinical relevance for lactation)

Key Derived Parameters

Half-life (t½): Time for plasma concentration to halve. ~5 half-lives = steady state / elimination.
Clearance (CL): Volume of blood cleared of drug per unit time. CL = 0.693 × Vd / t½.
Bioavailability (F): Fraction reaching systemic circulation. IV = 100%. Oral <100% due to first-pass + incomplete absorption.
Therapeutic window: Concentration range: effective but not toxic. Narrow window = therapeutic drug monitoring (TDM).

Why This Matters for You

Take with/without food as directed (affects absorption)
Space interacting medications
Report all supplements/herbals (St. John's wort = potent CYP3A4 inducer)
Renal/hepatic impairment → dose adjustment often needed
Age, genetics, pregnancy, disease states alter PK
Adherence = maintaining therapeutic concentrations

Pharmacodynamics (what drug does to body) + Pharmacokinetics (what body does to drug) = Clinical Effect.