Pharmacokinetics is the study of drug disposition in the body and focuses on the changes in drug plasma concentration. For any given drug and dose, the plasma concentration of the drug will rise and fall according to the rates of three processes: absorption, distribution, and elimination. Absorption of a drug refers to the movement of drug into the bloodstream, with the rate dependent on the physical characteristics of the drug and its formulation. Distribution of a drug refers to the process of a drug leaving the bloodstream and going into the organs and tissues. Elimination of a drug from the blood relies on two processes: biotransformation (metabolism) of a drug to one or more metabolites, primarily in the liver, and the excretion of the parent drug or its metabolites, primarily by the kidneys. The relationship between these processes is shown in Figure 2-1.

Drug Absorption

Drug absorption refers to the passage of drug molecules from the site of administration into the circulation. The process of drug absorption applies to all routes of administration, except for the topical route, in which drugs are applied directly on the target tissue, and intravenous administration, in which the drug is already in the circulation. Drug absorption requires that drugs cross one or more layers of cells and cell membranes. Drugs injected into the subcutaneous tissue and muscle bypass the epithelial barrier and are more easily absorbed through spaces between capillary endothelial cells. In the gut, lungs, and skin, drugs must first be absorbed through a layer of epithelial cells that have tight junctions. For this reason, drugs face a greater barrier to absorption after oral administration than after parenteral administration.

Processes of Absorption

Most drugs are absorbed by passive diffusion across a biologic barrier and into the circulation. The rate of absorption is proportional to the drug concentration gradient across the barrier and the surface area available for absorption at that site, known as Fick’s law. Drugs can be absorbed passively through cells either by lipid diffusion or by aqueous diffusion. Lipid diffusion is a process by which the drug dissolves in the lipid components of the cell membranes. This process is facilitated by a high degree of lipid solubility of the drug. Aqueous diffusion occurs by passage through aqueous pores in cell membranes. Because aqueous diffusion is restricted to drugs with low molecular weights, many drugs are too large to be absorbed by this process.

A few drugs are absorbed by active transport or by facilitated diffusion. Active transport requires a carrier molecule and a form of energy, provided by hydrolysis of the terminal high-energy phosphate bond of adenosine triphosphate (ATP). Active transport can transfer drugs against a concentration gradient. For example, the antineoplastic drug 5-fluorouracil undergoes active transport. Facilitated diffusion also requires a carrier molecule, but no energy is needed. Thus drugs or substances cannot be transferred against a concentration gradient but diffuse faster than without a carrier molecule present. Some cephalosporin antibiotics, such as cephalexin, undergo facilitated diffusion by an oligopeptide transporter protein located in intestinal epithelial cells.

Effect of pH on Absorption of Weak Acids and Bases

Many drugs are weak acids or bases that exist in both ionized and nonionized forms in the body. Only the nonionized form of these drugs is sufficiently soluble in membrane lipids to cross cell membranes (Box 2-1). The ratio of the two forms at a particular site influences the rate of absorption and is also a factor in distribution and elimination.

The protonated form of a weak acid is nonionized, whereas the protonated form of a weak base is ionized. The ratio of the protonated form to the nonprotonated form of these drugs can be calculated using the Henderson-Hasselbalch equation (see Box 2-1). The pKa is the negative log of the ionization constant, particular for each acidic or basic drug. At a pH equal to the pKa, equal amounts of the protonated and nonprotonated forms are present. If the pH is less than the pKa, the protonated form predominates. If the pH is greater than the pKa, the nonprotonated form predominates.

In the stomach, with a pH of 1, weak acids and bases are highly protonated. At this site, the nonionized form of weak acids (pKa = 3 to 5) and the ionized form of weak bases (pKa = 8 to 10) will predominate. Hence, weak acids are more readily absorbed from the stomach than are weak bases. In the intestines, with a pH of 7, weak bases are also mostly ionized, but much less so than in the stomach, and weak bases are absorbed more readily from the intestines than from the stomach.

However, weak acids can also be absorbed more readily from the intestines than from the stomach, despite their greater ionization in the intestines, because the intestines have a greater surface area than the stomach for absorption of the nonionized form of a drug, and this outweighs the influence of greater ionization in the intestines.

Drug Distribution

Drugs are distributed to organs and tissues via the circulation, diffusing into interstitial fluid and cells from the circulation. Most drugs are not uniformly distributed throughout total body water, and some drugs are restricted to the extracellular fluid or plasma compartment. Drugs with sufficient lipid solubility can simply diffuse through membranes into cells. Other drugs are concentrated in cells by the phenomenon of ion trapping, which is described further later. Drugs can also be actively transported into cells. For example, some drugs are actively transported into hepatic cells, where they may undergo enzymatic biotransformation.

Opposing the distribution of drugs to tissues are a number of ATP-driven drug efflux pumps, known as ABC transporters (ABC is an acronym for “ATP-binding cassette”). The most studied of these proteins, called permeability glycoprotein or P-glycoprotein (Pgp), is expressed on the luminal side of endothelial cells lining the intestines, brain capillaries, and a number of other tissues. Drug transport in the blood-to-lumen direction leads to a secretion of various drugs into the intestinal tract, thereby serving as a detoxifying mechanism. Pgp also serves to exclude drugs from the brain. The Pgp proteins exclude drugs from tissues throughout the body, including anticancer agents from tumors, leading to chemotherapeutic drug resistance. Inhibition of Pgp by amiodarone, erythromycin, propranolol, and other agents can increase tissue levels of these drugs and augment their pharmacologic effects (see Fig. 45-2).

Factors Affecting Distribution

Organ Blood Flow

The rate at which a drug is distributed to various organs after a drug dose is administered depends largely on the proportion of cardiac output received by the organs. Drugs are rapidly distributed to highly perfused tissues, namely the brain, heart, liver, and kidney, and this enables a rapid onset of action of drugs affecting these tissues. Drugs are distributed more slowly to less perfused tissues such as skeletal muscle and even more slowly to those with the lowest blood flow, such as skin, bone, and adipose tissue.

Plasma Protein Binding

Almost all drugs are reversibly bound to plasma proteins, primarily albumin, but also lipoproteins, glycoproteins, and β-globulins. The extent of binding depends on the affinity of a particular drug for protein-binding sites and ranges from less than 10% to as high as 99% of the plasma concentration. As the free (unbound) drug diffuses into interstitial fluid and cells, drug molecules dissociate from plasma proteins to maintain the equilibrium between free drug and bound drug. In general, acidic drugs bind to albumin and basic drugs to glycoproteins and β-globulins.

Plasma protein binding is saturable, and a drug can be displaced from binding sites by other drugs that have a high affinity for such sites. However, most drugs are not used at high enough plasma concentrations to occupy the vast number of plasma protein binding sites. There are a few agents that may cause drug interactions by competing for plasma protein binding sites, as highlighted in Chapter 4.

Drug Biotransformation

Drug biotransformation and excretion are the two processes responsible for the decline of the plasma drug concentration over time. Both of these processes contribute to the elimination of active drug from the body, and as discussed later in the chapter, clearance is a measure of the rate of elimination. Biotransformation, or drug metabolism, is the enzyme-catalyzed conversion of drugs to their metabolites. Most drug biotransformation takes place in the liver, but drug-metabolizing enzymes are found in many other tissues, including the gut, kidneys, brain, lungs, and skin.

First-Pass Biotransformation

Drugs that are absorbed from the gut reach the liver via the hepatic portal vein before entering the systemic circulation (Fig. 2-2). Many drugs, such as the antihypertensive agent felodipine (PLENDIL), are extensively converted to inactive metabolites during their first pass through the gut wall and liver, and have low bioavailability (see later) after oral administration. This phenomenon is called the first-pass effect. Drugs administered by the sublingual or rectal route undergo less first-pass metabolism and have a higher degree of bioavailability than do drugs administered by the oral route.

Phases of Drug Biotransformation

Drug biotransformation can be divided into two phases, each carried out by unique sets of metabolic enzymes. In many cases, phase I enzymatic reactions create or unmask a chemical group required for a phase II reaction. In some cases, however, drugs bypass phase I biotransformation and go directly to phase II. Although some phase I drug metabolites are pharmacologically active, most phase II drug metabolites are inactive.

Phase I Biotransformation

Phase I biotransformation includes oxidative, hydrolytic, and reductive reactions (Fig. 2-3).

Oxidative Reactions

Oxidative reactions are the most common type of phase I biotransformation. They are catalyzed by enzymes isolated in the microsomal fraction of liver homogenates (the fraction derived from the endoplasmic reticulum) and by cytoplasmic enzymes.

The microsomal cytochrome P450 (CYP) monooxygenase system is a family of enzymes that catalyze the biotransformation of drugs with a wide range of chemical structures. The microsomal monooxygenase reaction requires the following: CYP (a hemoprotein); a flavoprotein that is reduced by nicotinamide adenine dinucleotide phosphate (NADPH), called NADPH CYP reductase; and membrane lipids in which the system is embedded. In the drug-oxidizing reaction, one atom of oxygen is used to form a hydroxylated metabolite of a drug, as shown in Figure 2-4, whereas the other atom of oxygen forms water when combined with electrons contributed by NADPH. The hydroxylated metabolite may be the end product of the reaction or serve as an intermediate that leads to the formation of another metabolite.

The most common chemical reactions catalyzed by CYP enzymes are aliphatic hydroxylation, aromatic hydroxylation, N-dealkylation, and O-dealkylation.

Many CYP isozymes have been identified and cloned, and their role in metabolizing specific drugs elucidated. Each isozyme catalyzes a different but overlapping spectrum of oxidative reactions. Most drug biotransformation is catalyzed by three CYP families named CYP1, CYP2, and CYP3. The different CYP families are likely related by gene duplication, and each family is divided into subfamilies, also clearly related by homologous protein sequences. The CYP3A subfamily catalyzes more than half of all microsomal drug oxidations.

Many drugs alter drug metabolism by inhibiting or inducing CYP enzymes, and drug interactions can occur when these drugs are administered concurrently with other drugs that are metabolized by CYP (see Chapter 4). Two examples of inducers of CYP are the barbiturate phenobarbital and the antitubercular drug rifampin. The inducers stimulate the transcription of genes encoding CYP enzymes, resulting in increased messenger RNA (mRNA) and protein synthesis. Drugs that induce CYP enzymes activate the binding of nuclear receptors to enhancer domains of CYP genes, increasing the rate of gene transcription.

A few drugs are oxidized by cytoplasmic enzymes. For example, ethanol is oxidized to aldehyde by alcohol dehydrogenase, and caffeine and the bronchodilator theophylline are metabolized by xanthine oxidase. Other cytoplasmic oxidases include monoamine oxidase, a site of action for some psychotropic medications.

Phase II Biotransformation

In phase II biotransformation, drug molecules undergo conjugation reactions with an endogenous substance such as acetate, glucuronate, sulfate, or glycine (Fig. 2-5). Conjugation enzymes, which are present in the liver and other tissues, join various drug molecules with one of these endogenous substances to form water-soluble metabolites that are more easily excreted. Except for microsomal glucuronosyltransferases, these enzymes are located in the cytoplasm. Most conjugated drug metabolites are pharmacologically inactive.


Since the completion of the Human Genome Project, it is now fully realized that there is a great degree of individual variation, called polymorphism, in the genes coding for drug-metabolizing enzymes. Modern genetic studies were triggered by rare fatalities in children being treating for leukemia using the thiopurine agent 6-mercaptopurine (6-MP). It was discovered that the children died as a result of drug toxicity because they expressed a faulty variant of thiopurine methyltransferase, the enzyme that metabolizes 6-MP.

Variations in Acetyltransferase Activity

Individuals exhibit slow or fast acetylation of some drugs because of genetically determined differences in N-acetyltransferase. Slow acetylators (SAs) were first identified by neuropathic effects of isoniazid, a drug to treat tuberculosis (see Chapter 41). These patients had higher plasma levels of isoniazid compared with other patients classified as rapid acetylators (RAs). The SA phenotype is autosomal recessive, although more than 20 allelic variants of the gene for N-acetyltransferase have been identified. In individuals with one wild-type enzyme and one faulty variant, an intermediate phenotype is observed. The distribution of these phenotypes varies from population to population. About 15% of Asians, 50% of Caucasians and Africans, and more than 80% of Mideast populations have the SA phenotype. Other drugs that may cause toxicity in the SA patient are sulfonamide antibiotics, the antidysrhythmic agent procainamide, and the antihypertensive agent hydralazine.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Pharmacokinetics

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