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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 several restrictive barriers en route to its target site. Following administration, the drug must be absorbed and 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 and drug-drug interactions.
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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 (i.e., molecular weight) and structural features, degree of ionization, the 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
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
FDA: Food and Drug Administration
GI: gastrointestinal
h: hours
k: a rate constant
MDR1: multidrug resistance protein
MEC: minimum effective concentration
min: minutes
PLLR: Pregnancy and Lactation Labeling Rule
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 ...