Key Pharmacokinetic Processes

Why This Matters

Pharmacokinetics answers the fundamental question: what does the body do to the drug? You're being tested on your ability to predict how drugs behave once they enter a patient—how quickly they'll work, how long they'll last, and why some patients need different doses than others. These concepts form the quantitative backbone of drug therapy, connecting abstract chemistry to real clinical decisions about dosing intervals, route selection, and patient safety.

The four core processes—absorption, distribution, metabolism, and excretion (ADME)—don't exist in isolation. They interact dynamically, and exam questions will push you to think about how changes in one process cascade through the others. Don't just memorize definitions—know what each parameter tells you about a drug's behavior and when you'd adjust therapy based on that information.

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The ADME Framework: How Drugs Move Through the Body

These four processes describe the complete journey of a drug molecule from administration to elimination. Each step represents a potential point of variability between patients and a target for drug interactions.

Absorption

• Entry into systemic circulation—the process by which a drug moves from its administration site into the bloodstream, determining how much drug is available to produce effects
• Rate-limiting factors include drug formulation, GI pH, blood flow to absorption site, and surface area—oral drugs face the most barriers
• Clinical relevance centers on onset of action; IV administration bypasses absorption entirely, providing 100% and immediate availability

Distribution

• Dispersion throughout body compartments—describes how a drug moves from blood into tissues, fluids, and ultimately to its site of action
• Protein binding to albumin and alpha-1 acid glycoprotein limits free drug available for effect; only unbound drug is pharmacologically active
• Tissue permeability varies dramatically—the blood-brain barrier excludes most drugs, while highly perfused organs (heart, liver, kidneys) receive drug rapidly

Metabolism

• Biotransformation converts lipophilic drugs into more water-soluble metabolites for elimination, primarily through hepatic cytochrome P450 enzymes
• Phase I reactions (oxidation, reduction, hydrolysis) often create active metabolites; Phase II reactions (conjugation) typically inactivate drugs
• Drug interactions frequently occur here—enzyme inducers speed metabolism while inhibitors slow it, dramatically altering drug levels

Excretion

• Renal elimination is the primary route for most drugs and metabolites, occurring through glomerular filtration, tubular secretion, and reabsorption
• Alternative routes include biliary excretion (with potential enterohepatic recirculation), pulmonary exhalation, and minor losses through sweat and saliva
• Kidney function directly impacts dosing—reduced GFR requires dose adjustments to prevent accumulation and toxicity

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Quantifying Drug Availability

These parameters help you calculate and predict how much drug actually reaches its target. They're essential for dosing calculations and understanding why the same dose produces different effects in different patients.

Bioavailability

• Fraction reaching systemic circulation (abbreviated F)—expressed as a percentage or decimal, with IV administration defined as 100% (F = 1)
• First-pass metabolism is the primary reason oral bioavailability falls below 100%; some drugs lose 90%+ of their dose before reaching circulation
• Dosing implications mean that switching routes requires recalculation—a drug with 50% oral bioavailability needs twice the oral dose to match an IV dose

First-Pass Effect

• Pre-systemic metabolism occurs when orally administered drugs pass through the gut wall and liver before reaching systemic circulation
• High extraction drugs like morphine, propranolol, and nitroglycerin have dramatically reduced oral bioavailability, explaining why nitroglycerin is given sublingually
• Bypassing strategies include sublingual, transdermal, rectal (lower rectum), and parenteral routes—all avoid the portal circulation

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Parameters That Guide Dosing Decisions

These calculated values translate pharmacokinetic theory into practical dosing. Master these relationships and you can predict how dose adjustments will affect drug levels.

Volume of Distribution

• Theoretical volume ($V_d$) represents the apparent space a drug occupies if distributed uniformly at plasma concentration—calculated as $V_d = \frac{\text{Dose}}{C_0}$
• Interpretation matters: small $V_d$ (3-5 L) suggests drug stays in plasma; large $V_d$ (>40 L) indicates extensive tissue binding or sequestration
• Loading dose calculations depend directly on $V_d$—drugs with large volumes of distribution require larger loading doses to achieve therapeutic levels quickly

Half-Life

• Time for 50% reduction in plasma concentration ($t_{1/2}$)—determines dosing frequency and time to reach steady state
• Mathematical relationship: $t_{1/2} = \frac{0.693 \times V_d}{CL}$, showing that half-life depends on both distribution and clearance
• Clinical rule: after 4-5 half-lives, drug reaches steady state (accumulation) or is essentially eliminated (washout)

Clearance

• Volume cleared per unit time ($CL$)—the most important parameter for determining maintenance dose, expressed in L/hr or mL/min
• Organ-specific clearance (hepatic, renal) can be measured separately; total clearance equals the sum of all elimination pathways
• Maintenance dose relationship: $\text{Dose rate} = CL \times C_{ss}$, meaning higher clearance requires higher doses to maintain the same concentration

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Achieving Therapeutic Goals

These concepts connect individual parameters to the ultimate goal: maintaining effective drug concentrations over time.

Steady-State Concentration

• Equilibrium point ($C_{ss}$) where rate of drug input equals rate of elimination—the target for chronic therapy
• Time to steady state equals 4-5 half-lives regardless of dose or dosing interval; this cannot be shortened except by giving a loading dose
• Fluctuation between peak and trough levels depends on dosing interval relative to half-life—more frequent dosing produces smoother levels

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Quick Reference Table

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Self-Check Questions

1. A drug has a half-life of 6 hours. How long will it take to reach steady state with regular dosing, and what percentage of steady state is achieved after 3 half-lives?

2. Compare volume of distribution and clearance: which parameter determines loading dose, which determines maintenance dose, and why?

3. Two drugs have identical clearance values, but Drug A has a $V_d$ of 10 L while Drug B has a $V_d$ of 200 L. Which has the longer half-life, and how would their dosing frequencies differ?

4. A patient with severe liver disease is prescribed a drug with high first-pass metabolism. Would you expect the oral bioavailability to increase or decrease compared to a healthy patient? Explain the mechanism.

5. If an FRQ asks you to explain why a patient on chronic phenytoin therapy develops toxicity after starting a new medication, which pharmacokinetic process and parameter should you focus on, and what specific mechanism would you describe?