Distribution, Metabolism & Excretion

Two patients receive the same dose of the same drug — one gets relief, the other gets toxic. The difference isn't absorption; it's what happens after the drug hits the bloodstream.

Once a drug is absorbed, three pharmacokinetic processes determine how much active drug reaches the target and how long it stays. Distribution is the drug traveling from the bloodstream into tissues. It depends on blood flow (highly perfused organs like the brain, liver, and kidneys get drug first), protein binding (only the unbound or "free" fraction is pharmacologically active), and lipid solubility (lipophilic drugs cross the blood-brain barrier and accumulate in fat, prolonging their effects in obese patients). A patient with low albumin — think liver disease, malnutrition, or burns — has more free drug circulating, raising toxicity risk even at standard doses. Metabolism (biotransformation) occurs primarily in the liver via cytochrome P450 enzymes. First-pass metabolism can inactivate a large portion of an oral drug before it ever reaches systemic circulation — this is why some drugs require higher oral doses than IV doses. Hepatic impairment slows metabolism, effectively increasing drug levels and duration. Excretion removes active drug and metabolites, mainly through the kidneys. Renal clearance depends on glomerular filtration rate; a declining GFR (as in older adults or renal disease) means drugs accumulate. Creatinine clearance and serum creatinine guide dose adjustments. Half-life — the time for plasma concentration to drop by 50% — integrates metabolism and excretion. Steady state is reached in approximately 4–5 half-lives.

Key Distinctions

Don't confuse protein binding with drug interactions — a highly protein-bound drug displaced by a competitor increases the free fraction of the displaced drug, raising its toxicity risk; that topic is covered under interactions, so here focus on albumin status as the independent variable. Students mix up first-pass metabolism (a liver process reducing bioavailability of oral drugs) with hepatic metabolism of drugs already in systemic circulation — they're related but distinct concepts. Half-life is not the same as duration of action; a drug can have active metabolites that extend therapeutic effect beyond what half-life predicts.

Clinical Pearl

Low albumin + high protein-binding drug = toxicity waiting to happen. Always check albumin and creatinine before assuming a "normal" dose is safe.