Chapter 2 · Module 4 of 5 · Pharmacokinetics

Elimination

Renal glomerular filtration, tubular secretion and reabsorption, dose adjustment in renal impairment, biliary excretion, enterohepatic recirculation, and minor elimination routes

Glomerular filtration eliminates only the free (unbound) fraction of a drug; protein-bound drug is retained; eGFR estimates filtration capacity and guides dose adjustment thresholds; secretion via OAT and OCT transporters adds active elimination of organic anions and cations regardless of protein binding
Tubular reabsorption of lipophilic un-ionized drug reduces net renal excretion; ion trapping exploits pH to convert drug to its ionized (non-reabsorbable) form in the tubule — urinary alkalinization traps weak acids like salicylate (overdose antidote), and urinary acidification traps weak bases like amphetamine
Renal impairment demands systematic drug management: avoid entirely if drug or toxic metabolite causes direct harm (metformin, meperidine, nitrofurantoin, NSAIDs); reduce dose for drugs with accumulated parent compound; extend interval for concentration-dependent drugs (aminoglycosides); and monitor levels when pharmacokinetics are too variable to predict without measurement
Biliary excretion applies to molecules >500–600 Da (rifampin, digoxin antibody fragment, many glucuronide conjugates); enterohepatic recirculation — gut bacteria hydrolyze biliary conjugates, releasing free drug for reabsorption — prolongs drug action and can be interrupted by cholestyramine or activated charcoal
Pulmonary elimination removes volatile agents (inhalational anesthetics, ethanol) and is directly proportional to their vapor pressure; breast milk concentrates basic, lipophilic, low-protein-bound drugs — the M:P ratio and the LactMed database guide prescribing decisions in nursing mothers

Sections 1 & 2 — Renal Elimination Mechanisms

Sections 1 & 2

Filtration, Secretion, Reabsorption, and Ion Trapping

Glomerular Filtration and Secretion

Inputs to Tubular Fluid

Filtration: only FREE (unbound) drug is filtered; protein-bound fraction is retained
eGFR estimates filtration capacity — Cockcroft-Gault and CKD-EPI equations used clinically
Tubular secretion: OAT (organic anion transporter) and OCT (organic cation transporter) actively secrete regardless of protein binding
OAT substrates: penicillins, methotrexate, furosemide, NSAIDs
OCT substrates: metformin, procainamide, ranitidine
Probenecid blocks OAT → delays penicillin secretion (historically used to extend antibiotic action)

Tubular Reabsorption and Ion Trapping

Outputs from Tubular Fluid

Lipophilic un-ionized drug passively reabsorbs from tubule back to blood — reduces net renal excretion
Ion trapping: ionized drug cannot cross tubular membrane → trapped in urine
Urinary alkalinization: converts weak acids to ionized form → traps in urine → faster excretion
Clinical use: salicylate overdose — sodium bicarbonate alkalinizes urine → traps salicylate
Urinary acidification: traps weak bases (amphetamine, phencyclidine) — now rarely used clinically

Section 3 — Dose Adjustment in Renal Impairment

Section 3

Five Management Strategies by Drug and Impairment Category

Strategy	Approach	Examples	Rationale
Avoid entirely	Use alternative drug	Metformin (lactic acidosis), meperidine (normeperidine seizures), nitrofurantoin (inadequate urinary concentration), NSAIDs (further renal injury)	Drug or toxic metabolite causes harm in renal failure regardless of dose reduction
Reduce dose	Lower dose, same interval	Digoxin, beta-lactam antibiotics, gabapentin, many antivirals	Maintains steady-state exposure; prevents accumulation toxicity
Extend interval	Normal dose, longer interval	Aminoglycosides, vancomycin	Preserves peak concentration for efficacy (concentration-dependent killing); reduces trough-related toxicity
Monitor levels	Dose guided by measured plasma concentration	Vancomycin, aminoglycosides, digoxin, lithium, phenytoin (with albumin correction)	Variable pharmacokinetics in renal failure; TDM guides dosing precisely
No adjustment	Standard dosing	Azithromycin, doxycycline, linezolid, clindamycin, most macrolides	Primarily hepatic or biliary elimination; renal accumulation not clinically significant

Renal failure alters more than filtration: Uremic toxins displace drugs from albumin (increases free phenytoin fraction — Sheiner-Tozer correction needed); drug metabolites accumulate; gut CYP3A4 may be altered. Do not assume that only filtration-dependent drugs need adjustment in severe renal failure.

Sections 4 & 5 — Biliary Excretion and Enterohepatic Recirculation

Sections 4 & 5

Biliary Elimination and Enterohepatic Recirculation

Biliary Excretion

Large Molecules and Conjugates

Molecular weight threshold: ~500–600 Da favors biliary excretion over renal
Phase II glucuronide and sulfate conjugates excreted prominently in bile
Examples: rifampin, digoxin-specific antibody fragments, many hormones
Obstruction (cholestasis) impairs biliary excretion → drug accumulation even with normal renal function

Enterohepatic Recirculation (EHR)

Bile → Gut → Reabsorption → Liver

Biliary conjugate enters intestine → gut bacteria hydrolyze to free drug → reabsorbed into portal circulation
Effect: prolongs drug action and expands apparent half-life
Drugs subject to EHR: ethinyl estradiol (oral contraceptives), morphine, bile acids, some antibiotics
Cholestyramine or activated charcoal can interrupt EHR → shortens duration; therapeutic use in colchicine toxicity and life-threatening drug intoxication

Section 6 — Other Routes of Elimination

Section 6

Pulmonary, Mammary, Salivary, and Skin Elimination

Pulmonary Elimination

Volatile Drugs Exhaled

Applies to volatile agents: inhalational anesthetics, ethanol
Elimination rate proportional to vapor pressure and respiratory rate
Hyperventilation accelerates elimination of inhalational anesthetics
Basis of breath alcohol testing: blood alcohol ∝ exhaled concentration

Breast Milk Excretion

Risk in Nursing Infants

Breast milk is slightly acidic → concentrates basic, lipophilic, low-protein-bound drugs
M:P ratio >1 indicates concentration in milk relative to plasma
High-risk: lithium, cytotoxic agents, radioactive compounds, amiodarone
LactMed database (NIH/NLM) provides evidence-based safety assessments
Most therapeutic drugs compatible with breastfeeding at standard doses

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Katzung BG, ed.	Basic and Clinical Pharmacology, 15th edition	McGraw-Hill, 2021
Brunton LL, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th edition	McGraw-Hill, 2023
Rowland M, Tozer TN	Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, 4th edition	Lippincott Williams & Wilkins, 2011
Brunton LL, Hilal-Dandan R, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th edition	McGraw-Hill, 2018
Aronoff GR, et al.	Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th edition	American College of Physicians, 2007
Nolin TD, et al.	ESRD-associated alterations in drug disposition: mechanisms and clinical implications	Seminars in Dialysis, 2010; 23(3):250–257
Giacomini KM, et al.	Membrane transporters in drug development	Nature Reviews Drug Discovery, 2010; 9(3):215–236
Klaassen CD, Aleksunes LM	Xenobiotic, bile acid, and cholesterol transporters: function and regulation	Pharmacological Reviews, 2010; 62(1):1–96
Hale TW	Medications and Mothers' Milk, 19th edition	Springer, 2021
Sager JE, et al.	Physiologically based pharmacokinetic modeling and simulation approaches: a systematic review of published models, applications, and model verification	Drug Metabolism and Pharmacokinetics, 2015; 30(1):3–25