Pharmacokinetics: ADME, Drug Absorption, Distribution, Metabolism, and Excretion

Introduction

Pharmacokinetics describes the movement of drugs through the body over time, encompassing four major processes: absorption, distribution, metabolism, and excretion (ADME). Understanding pharmacokinetics is essential for determining appropriate dosing regimens, predicting drug concentrations, managing drug interactions, and individualizing therapy.

Drug Absorption

Mechanisms of Drug Absorption

Mechanism	Description	Energy Required	Saturation	Examples
Passive diffusion	Drug moves down concentration gradient through lipid bilayer	No	No	Most lipophilic drugs (NSAIDs, benzodiazepines)
Facilitated diffusion	Carrier-mediated transport down concentration gradient	No	Yes	Vitamin B12, some amino acid analogs
Active transport	Carrier-mediated against concentration gradient	Yes (ATP)	Yes	Digoxin (P-gp), some antibiotics
Endocytosis	Cell membrane engulfs drug molecules	Yes	Yes	Large molecules, vitamin B12-intrinsic factor complex
Paracellular transport	Drug passes between cells through tight junctions	No	No	Small hydrophilic drugs (atenolol)

Factors Affecting Absorption

Factor	Effect on Absorption	Examples
Lipophilicity	More lipophilic drugs absorb better	Propranolol (highly lipophilic, well absorbed)
Molecular weight	Smaller molecules (<500 Da) absorb better	Most drugs are <500 Da
Degree of ionization	Unionized forms absorb better (pH-partition hypothesis)	Weak acids absorb in stomach (acidic pH), weak bases in intestine (alkaline pH)
Gastrointestinal pH	pH varies from 1-2 (stomach) to 6-8 (ileum)	Enteric coating protects drugs degraded by stomach acid
Blood flow	High blood flow increases absorption rate	Vasodilation increases, vasoconstriction decreases absorption
Surface area	Larger surface area increases absorption	Small intestine has largest surface area (200 m2)
Gastric emptying rate	Faster emptying increases absorption rate	Delayed by food, opioids; accelerated by metoclopramide
Food interactions	Can increase or decrease absorption	Grapefruit juice inhibits CYP3A4 (increases drug levels); calcium binds tetracyclines (decreases absorption)

Bioavailability (F)

Parameter	Definition	Formula	Clinical Significance
Absolute bioavailability	Fraction of drug reaching systemic circulation after non-IV administration	F = AUC(oral)/AUC(IV) x 100%	Determines oral dose needed
Relative bioavailability	Comparison of two non-IV formulations	F(rel) = AUC(test)/AUC(reference) x 100%	Bioequivalence studies
First-pass effect	Drug metabolized in liver or gut before reaching systemic circulation	Reduces oral bioavailability	High first-pass: propranolol, lidocaine, nitroglycerin
Sublingual/buccal	Avoids first-pass metabolism	Higher bioavailability than oral	Nitroglycerin, buprenorphine, naltrexone

Distribution

Volume of Distribution (Vd)

Vd Value	Interpretation	Examples
3-5 L (plasma volume)	Drug confined to plasma	Heparin, warfarin (highly protein-bound)
12-20 L (extracellular fluid)	Drug distributed in extracellular space	Aminoglycosides, lithium
25-40 L (total body water)	Drug distributed throughout body water	Ethanol, theophylline
>40 L (exceeds body water)	Extensive tissue binding/sequestration	Digoxin (500 L), chloroquine (13,000 L)

Factors Affecting Distribution

Factor	Description	Clinical Impact
Plasma protein binding	Drugs bind to albumin, alpha-1-acid glycoprotein, lipoproteins	Only unbound drug is pharmacologically active
Tissue binding	Drugs accumulate in tissues (adipose, muscle, bone)	Prolonged effects; reservoir function
Blood-brain barrier	Tight junctions, efflux transporters (P-gp) limit CNS penetration	L-DOPA crosses (Parkinson’s); many antibiotics do not
Placental barrier	Drugs can cross placenta (molecular weight, lipophilicity)	Teratogenicity risk during pregnancy
Body composition	Fat/lean ratio, total body water	Obese patients need dose adjustments for lipophilic drugs
Age	Neonates: higher body water, lower protein binding	Increased Vd for water-soluble drugs
Organ perfusion	Highly perfused organs (brain, liver, kidney) receive drug rapidly	Distribution phase accounts for rapid initial effect

Metabolism (Biotransformation)

Phase I Reactions

Reaction	Enzyme System	Location	Example
Oxidation	CYP450 (CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2)	Liver (primarily), intestine, lung, kidney	Diazepam to nordazepam (CYP3A4)
Reduction	Reductases, CYP450	Liver	Warfarin to reduced metabolites
Hydrolysis	Esterases, amidases	Liver, plasma, tissues	Aspirin to salicylic acid

Phase II Reactions (Conjugation)

Reaction	Conjugating Agent	Transferase	Example
Glucuronidation	UDP-glucuronic acid	UGT (UGT1A1, UGT2B7)	Morphine to morphine-6-glucuronide (active)
Sulfation	PAPS (sulfate donor)	Sulfotransferase	Acetaminophen (minor pathway)
Acetylation	Acetyl-CoA	NAT2	Isoniazid, procainamide
Methylation	SAMe (methyl donor)	Methyltransferases	L-DOPA, catecholamines
Glutathione conjugation	Glutathione	GST	Acetaminophen (toxic metabolite detoxification)

CYP450 Enzyme System

Isoenzyme	Fraction of Drug Metabolism	Substrates (Examples)	Inhibitors	Inducers
CYP3A4/5	~50%	Statins (atorvastatin, simvastatin), macrolides, CCBs, benzodiazepines, imatinib	Grapefruit juice, ketoconazole, ritonavir, clarithromycin	Rifampin, carbamazepine, phenytoin, St. John’s Wort
CYP2D6	~20%	Codeine, tramadol, antidepressants (TCAs, SSRIs), antipsychotics, beta-blockers	Fluoxetine, paroxetine, quinidine, bupropion	Not significantly induced
CYP2C9	~15%	Warfarin, phenytoin, glipizide, losartan, NSAIDs	Amiodarone, fluconazole, metronidazole	Rifampin, carbamazepine
CYP2C19	~8%	Omeprazole, clopidogrel, citalopram, diazepam	Fluvoxamine, omeprazole, ticlopidine	Rifampin, carbamazepine
CYP1A2	~4%	Theophylline, caffeine, clozapine, olanzapine, tizanidine	Fluvoxamine, ciprofloxacin, oral contraceptives	Smoking, carbamazepine, phenytoin

First-Pass Metabolism

Drug	Oral Bioavailability	Mechanism	Clinical Implication
Propranolol	25%	High hepatic extraction (CYP2D6, CYP1A2)	Oral dose 10x IV dose
Nitroglycerin	<10%	Extensive hepatic metabolism	Sublingual/transdermal route preferred
Lidocaine	<5%	Extensive hepatic metabolism	IV only for antiarrhythmic use
Verapamil	20-35%	Hepatic metabolism	Individualized dosing
Morphine	20-40%	Glucuronidation in gut and liver	Significant interpatient variability

Excretion

Renal Excretion

Process	Description	Direction	Examples
Glomerular filtration	Passive filtration of unbound drug	Drugs moved from blood to filtrate	All unbound drugs (size <20 kDa)
Tubular reabsorption	Drug moves from filtrate back to blood	Passive (or active) reabsorption	Lipophilic drugs in distal tubule
Tubular secretion	Active transport from blood to filtrate	Secretion into tubule	Weak acids (penicillin, probenecid), weak bases (procainamide, metformin)

Factors Affecting Renal Excretion

Factor	Effect	Clinical Example
Renal function	Decreased GFR reduces excretion	Dose adjustment of renally eliminated drugs (aminoglycosides, digoxin)
Urine pH	Acidic urine promotes excretion of weak bases; alkaline urine promotes excretion of weak acids	Alkalinization for salicylate overdose; acidification for amphetamine overdose
Protein binding	Only unbound drug is filtered	Warfarin (99% bound) not filtered; gentamicin (low binding) extensively filtered
Competition for secretion	Drugs can compete for OAT/OCT transporters	Probenecid delays penicillin excretion (therapeutic use)

Non-Renal Excretion

Route	Mechanism	Drugs
Biliary excretion	Active transport into bile (MRP2, P-gp, BCRP)	Rifampin, ceftriaxone, digoxin, statins
Enterohepatic recirculation	Drug excreted in bile, reabsorbed in intestine	Oral contraceptives, morphine (prolongs half-life)
Pulmonary excretion	Volatile drug exhaled in breath	Anesthetic gases, ethanol (small amount)
Sweat/saliva/breast milk	Passive diffusion	Lithium, potassium iodide; many drugs appear in breast milk

Half-Life and Clearance

Elimination Half-Life (t1/2)

Half-Life Range	Dosing Interval Examples	Drugs
2-6 hours	3-4x daily	Penicillin, levodopa, metformin, furosemide
6-12 hours	2-3x daily	Atenolol, metoprolol, sulfamethoxazole
12-24 hours	Once daily	Atorvastatin, ibuprofen, losartan, omeprazole
24-72 hours	Once daily (some loading dose needed)	Warfarin (40h), amiodarone (58 days), fluoxetine (4-6 days), digoxin (36h)

Therapeutic Drug Monitoring (TDM)

Drug	Therapeutic Range	Toxic Level	Sampling Time
Digoxin	0.8-2.0 ng/mL	>2.0 ng/mL	At least 6-8h post-dose (trough)
Phenytoin	10-20 mcg/mL	>20 mcg/mL	Trough (just before next dose)
Vancomycin	10-20 mcg/mL (trough)	>20 mcg/mL	Trough (just before 4th dose)
Lithium	0.6-1.2 mEq/L	>1.5 mEq/L	12h post-dose
Gentamicin	Peak: 5-10 mcg/mL; Trough: <2 mcg/mL	Peak >12, Trough >2	Peak 30 min post-infusion; Trough pre-dose
Theophylline	5-15 mcg/mL	>20 mcg/mL	Trough or anytime (long half-life)

Conclusion

Pharmacokinetics provides the quantitative framework for understanding drug behavior in the body. Key parameters (bioavailability, volume of distribution, clearance, half-life) guide dosing decisions, route selection, and therapeutic monitoring. Understanding ADME processes, including CYP450 metabolism and drug transporters, is essential for predicting and managing drug interactions, toxicity, and interpatient variability.