Chapter 1 · Module 2 of 6 · General Principles

Pharmacokinetics: How the Body Handles Drugs

The four processes — absorption, distribution, metabolism, and elimination — that determine how much drug reaches its target, when, and for how long

Absorption determines how much of an administered dose reaches the systemic circulation; oral bioavailability is reduced by the first-pass effect, in which the liver metabolizes a fraction of absorbed drug before it can reach target organs
Distribution describes how widely a drug spreads from plasma into tissues; volume of distribution and plasma protein binding govern how much free drug is available at the receptor, and drugs with very large volumes of distribution cannot be removed by dialysis
Metabolism — primarily in the liver via cytochrome P450 enzymes — converts lipophilic drugs into more water-soluble forms through Phase I functionalization and Phase II conjugation; prodrugs require metabolic activation and may fail in hepatic impairment
Elimination half-life is the most clinically useful pharmacokinetic parameter: it determines dosing frequency, time to steady state (4–5 half-lives), and washout time after a drug is stopped
Hepatic and renal impairment each alter pharmacokinetics in predictable ways that require systematic dose adjustment — the same framework of ADME applies to every drug-disease interaction encountered in clinical practice

Sections 1–4 — The Four Pharmacokinetic Processes

ADME Overview

Absorption · Distribution · Metabolism · Elimination

Absorption

Drug moves from administration site into blood. Oral route subject to first-pass effect in liver.

Distribution

Drug spreads from blood into tissues. Extent reflects lipophilicity, protein binding, and tissue affinity.

Metabolism

Liver enzymes convert lipophilic drug to water-soluble form via Phase I then Phase II reactions.

Elimination

Drug and metabolites excreted, primarily by kidneys into urine. Half-life governs the rate.

Sections 1 & 2 — Absorption and Distribution

Sections 1 & 2

Absorption and Distribution

First-Pass Effect and Bioavailability

Oral drug absorbed into portal circulation
Passes through liver before reaching systemic blood
Liver enzymes metabolize a fraction on first pass
Reduces oral bioavailability below 100%
Sublingual and IV routes bypass first-pass entirely
IV administration = 100% bioavailability by definition
Prototype: nitroglycerin — therapeutically inactive orally

Volume of Distribution and Protein Binding

V_D describes how widely drug distributes into tissues
Small V_D → drug stays in plasma (e.g., warfarin)
Large V_D → drug accumulates in tissues
Very large V_D → dialysis cannot remove drug effectively
Only free (unbound) drug is pharmacologically active
Low albumin increases free fraction of protein-bound drugs
BBB requires lipophilicity and small molecular size to cross

Section 3 — Drug Metabolism

Section 3

Drug Metabolism — Phase I, Phase II, and Prodrugs

Phase I

Functionalization — make the drug more polar

Oxidation, reduction, or hydrolysis introduces or exposes a polar group. Carried out primarily by CYP enzymes in the liver. May produce active metabolites or begin inactivation. Metabolism does not always mean inactivation — some drugs yield pharmacologically active Phase I products.

Phase II

Conjugation — attach a water-soluble group for excretion

Glucuronic acid, sulfate, or acetyl group is attached to the drug or Phase I metabolite. Product is highly water-soluble, typically inactive, and readily excreted by kidneys or bile. Completes the conversion of a lipophilic drug into an eliminable form.

Prodrug

Inactive until metabolized — requires hepatic activation

Prodrugs are converted by metabolic reactions into the active compound. Example: enalapril (inactive) → enalaprilat (active ACE inhibitor). Designed to improve absorption, mask taste, or enhance tissue selectivity. Hepatic impairment may block activation — drug appears ineffective despite adequate absorption.

Section 4 — Elimination and Half-Life

Section 4

Half-Life and Steady State

Drug concentration remaining after each half-life

t½ ×1

50%

t½ ×2

25%

t½ ×3

12.5%

t½ ×4

6.25%

t½ ×5

3.1%

Steady state is reached after 4–5 half-lives of regular dosing — the same rule applies in reverse for drug washout after stopping. Loading doses compress time to therapeutic levels when waiting 4–5 half-lives is not clinically acceptable.

Section 5 — Pharmacokinetics in Clinical Practice

Section 5

Clinical Pharmacokinetic Adjustments

Hepatic Impairment

Reduced Phase I and II metabolism → drug accumulates
Reduced albumin → increased free fraction of protein-bound drugs
Reduced first-pass effect → increased oral bioavailability
Prodrugs may fail to activate
Standard doses of high-extraction drugs can cause toxicity

Renal Impairment

Renally cleared drugs accumulate with repeated dosing
Effective half-life is prolonged
Dose reduction or interval extension required
eGFR guides adjustment — specific thresholds per drug
Dialysis only removes drugs with small V_D

Author / Source	Title	Publication
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
Ritter JM, Flower R, Henderson G, Loke YK, MacEwan D, Rang HP	Rang & Dale's Pharmacology, 9th edition	Elsevier, 2019
Rowland M, Tozer TN	Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, 4th edition	Lippincott Williams & Wilkins, 2011
Atkinson AJ Jr, Huang SM, Lertora JJL, Markey SP, eds.	Principles of Clinical Pharmacology, 3rd edition	Academic Press, 2012
Wilkinson GR	Drug metabolism and variability among patients in drug response	New England Journal of Medicine, 2005; 352(21):2211–2221
Brunton LL, Hilal-Dandan R, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th edition	McGraw-Hill, 2018
Waller DG, Sampson AP	Medical Pharmacology and Therapeutics, 5th edition	Elsevier, 2018