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INTRODUCTION

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The human body restricts access to foreign molecules; therefore, to reach its target within the body and have a therapeutic effect, a drug molecule must cross a number of restrictive barriers en route to its target site. Following administration, the drug must be absorbed and then distributed, usually via vessels of the circulatory and lymphatic systems; in addition to crossing membrane barriers, the drug must survive metabolism (primarily hepatic) and elimination (by the kidney and liver and in the feces). ADME, the absorption, distribution, metabolism, and elimination of drugs, are the processes of pharmacokinetics (Figure 2–1). Understanding these processes and their interplay and employing pharmacokinetic principles increase the probability of therapeutic success and reduce the occurrence of adverse drug events.

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Figure 2–1

The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. Possible distribution and binding of metabolites in relation to their potential actions at receptors are not depicted.

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The absorption, distribution, metabolism, and excretion of a drug involve its passage across numerous cell membranes. Mechanisms by which drugs cross membranes and the physicochemical properties of molecules and membranes that influence this transfer are critical to understanding the disposition of drugs in the human body. The characteristics of a drug that predict its movement and availability at sites of action are its molecular size and structural features, degree of ionization, relative lipid solubility of its ionized and nonionized forms, and its binding to serum and tissue proteins. Although physical barriers to drug movement may be a single layer of cells (e.g., intestinal epithelium) or several layers of cells and associated extracellular protein (e.g., skin), the plasma membrane is the basic barrier.

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ABBREVIATIONS

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Abbreviations

ABC: ATP-binding cassette

ACE: angiotensin-converting enzyme

AUC: area under the concentration-time curve of drug absorption and elimination

BBB: blood-brain barrier

CL: clearance

CNS: central nervous system

CNT1: concentrative nucleoside transporter 1

Cp: plasma concentration

CSF: cerebrospinal fluid

Css: steady-state concentration

CYP: cytochrome P450

F: bioavailability

GI: gastrointestinal

h: hours

k: a rate constant

MDR1: multidrug resistance protein

MEC: minimum effective concentration

min: minutes

SLC: solute carrier

T, t: time

t1/2: half-life

V: volume of distribution

Vss: volume of distribution at steady state

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PASSAGE OF DRUGS ACROSS MEMBRANE BARRIERS

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The Plasma Membrane Is Selectively Permeable

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The plasma membrane consists of a bilayer of amphipathic lipids with their hydrocarbon chains oriented inward to the center of the bilayer to form a continuous hydrophobic phase, with their hydrophilic heads oriented outward. Individual lipid molecules in the bilayer vary according to the particular membrane and can move laterally and organize themselves into microdomains (e.g., regions with sphingolipids and cholesterol, forming lipid rafts), endowing the membrane with ...

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