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Absorption is the process by which a xenobiotic enters the body. A xenobiotic must reach the bloodstream and then be distributed to the site or sites of action to cause a systemic effect. Both the rate (ka) and extent of absorption (F) are measurable and important determinants of toxicity. The rate of absorption often predicts the onset of action and relies on dosage form, and the extent of absorption (bioavailability) often predicts the intensity of the effect and depends in part on first-pass effects.36,37 Figure 9–1 depicts how changes in the rate of absorption may affect toxicity when the bioavailability is held constant versus how toxicity may be affected by changes in bioavailability when the rate of absorption is held constant.
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The route by which the xenobiotic enters the body significantly affects both the rate and extent of absorption. As an approximation, the rate of absorption proceeds in the following order from fastest to slowest: intravenous (IV), inhalation > sublingual > intramuscular, subcutaneous, intranasal, oral > cutaneous, rectal. After the oral intake of 200 mg (0.59 mmole) of cocaine hydrochloride, the onset of action is 20 minutes, with an average peak concentration of 200 ng/mL.71 In marked contrast, smoking 200 mg (0.66 mmole) of cocaine freebase results in an onset of action of 8 seconds and a peak concentration of 640 ng/mL. When administered IV as 200 mg cocaine hydrochloride, it then has an onset of action of 30 seconds and a peak concentration of 1000 ng/mL.71
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A xenobiotic must diffuse through a number of membranes before it can reach its site of action. Figure 9–2 shows the number of membranes through which a xenobiotic typically diffuses. Membranes are predominantly composed of phospholipids and cholesterol in addition to other lipid compounds.54 A phospholipid is composed of a polar head and a fatty acid tail, which are arranged in membranes so that the fatty acid tails are inside and the polar heads face outward in a mirror image.58 Proteins are found on both sides of the membranes and may traverse the membrane.54 These proteins may function as receptors and channels. Pores are found throughout the membranes. The principles relating to diffusion apply to absorption, distribution, certain aspects of elimination, and each mechanism that permits a xenobiotic to be transported through a membrane.
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Transport through membranes occurs via (1) passive diffusion; (2) filtration or bulk flow, which is most important in renal and biliary secretion as the mechanism of transport associated with the movement of molecules with a molecular weight less than 100 Da, with water directly through aquapores; (3) carrier-mediated active or facilitated transport, which is saturable; and (4) rarely, endocytosis (Fig. 9–2). Most xenobiotics traverse membranes via simple passive diffusion. The rate of diffusion is determined by the Fick’s law of diffusion (Equation 9–1):
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D = diffusion coefficient
A = surface area of the membrane
h = membrane thickness
K = partition coefficient
C1 − C2 = difference in concentrations of the xenobiotic on each side of the membrane
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The driving force for passive diffusion is the difference between the concentrations of the xenobiotic on the opposing sides of the membrane. D is a constant for each xenobiotic and is derived when the difference in concentrations between the two sides of the membrane is one. The larger the surface area A, the higher the rate of diffusion. Most ingested xenobiotics are absorbed more rapidly in the small intestine than in the stomach because of the tremendous increase in surface area created by the presence of microvilli. The partition constant or ratio (previously called the coefficient) Kow represents the lipid-to-water partitioning of the nonionized xenobiotic with pH adjustment to favor nonionized xenobiotic. To a substantial degree, the more lipid soluble a xenobiotic is, the more easily it crosses membranes. The logarithm of the Kow is known as the log P. The distribution constant or ratio represents the lipid-to-water partitioning of the sum of the nonionized plus ionized in the octanol and water phase and is pH dependent. The logarithm of the distribution constant is called log D and is most useful when measured at physiologic pH. Membrane thickness (h) is inversely proportional to the rate at which a xenobiotic diffuses through the membrane. Xenobiotics that are uncharged, nonpolar, of low molecular weight, and of the appropriate lipid solubility have the highest rates of passive diffusion.
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The extent of ionization of weak electrolytes (weak acids and weak bases) affects their rate of passive diffusion. Nonpolar and uncharged molecules penetrate faster. The Henderson-Hasselbalch relationship is used to determine the degree of ionization. An acid (HA), by definition, gives up a proton, and a base (B) accepts a proton. Acids and bases can be nonionized (uncharged, molecular, free), positively charged (cationic), or negatively charged (anionic). Aspirin and phenobarbital are uncharged acids (RCOOH), and pseudoephedrine HCl is a cationic acid. Morphine, amphetamine, and amitriptyline are nonionized bases (RNH2), and sodium valproate is an anionic base. The equilibrium dissociation constants Ka and Kb can then be described. Ka × Kb = Kw, and Kw is the dissociation constant of water. Because these numbers are difficult to work with, they are transformed using logarithms. By Equations 9–2A and 9–2B:
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To work with these numbers in a more comfortable fashion, the negative log of both sides is determined. The results are given in Equations 9–3A and 9–3B.
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By definition, the negative log of [H+] is expressed as pH, and the negative log of Ka is pKa. Rearranging the equations gives the familiar forms of the Henderson-Hasselbalch equations, as shown in Equations 9–4A, 9–4B, and 9–4C:
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Because uncharged molecules traverse membranes more rapidly, it is understood that weak acids cross membranes more rapidly in an acidic environment, and weak bases move more rapidly in a basic environment. When the pH equals the pKa, half of the xenobiotic is charged, and half is uncharged. An acid with a low pKa is a strong acid, and a base with a low pKa is a weak base. For an acid, a pH less than the pKa favors the protonated or uncharged species facilitating membrane diffusion, and for a base, a pH greater than the pKa achieves the same result. Table 9–1 lists the pH of selected body fluids, and Fig. 9–3 illustrates the extent of charged versus uncharged xenobiotic at different pH and pKa and pKb values.
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Lipid solubility and ionization each have a distinct influence on absorption. Figure 9–4 demonstrates these characteristics for three different xenobiotics. Although the three xenobiotics have similar pKa and pKb values, their different partition constants result in different degrees of absorption from the stomach.
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Specialized transport mechanisms are either adenosine triphosphate (ATP) dependent to transport xenobiotics against a concentration gradient (ie, active transport) or ATP independent and lack the ability to transport against a concentration gradient (ie, facilitated transport). These transport mechanisms are of importance in numerous parts of the body, including the intestines, liver, lungs, kidneys, and biliary system. These same principles apply to a small number of lipid-insoluble molecules that resemble essential endogenous molecules.28,64 For example, 5-fluorouracil resembles pyrimidine and is transported by the same system, and thallium and lead are actively absorbed by the endogenous transport mechanisms that absorb and transport potassium and calcium, respectively. Filtration is generally considered to be of limited importance in the absorption of most xenobiotics but is substantially more important with regard to renal and biliary elimination. Endocytosis, which describes the encircling of a xenobiotic by a cellular membrane, is responsible for the absorption of large macromolecules such as the oral Sabin polio vaccine.64
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Gastrointestinal (GI) absorption is affected by xenobiotic-related characteristics such as dosage form, degree of ionization, partition constant, and patient factors (eg, GI blood flow; GI motility; and the presence or absence of food, ethanol, or other interfering substances such as calcium) (Fig. 9–5).
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The formulation of a xenobiotic is extremely important in predicting GI absorption. Disintegration and dissolution must precede absorption. Disintegration is usually much more rapid than dissolution except for modified-release products. Modified release is a broad term that encompasses products that are delayed-release and extended-release formulations. These modified-release formulations are designed to release the xenobiotic over a prolonged period of time to simulate the blood concentrations achieved with the use of a constant IV infusion. By definition, extended-release formulations decrease the frequency of drug administration by at least 50% compared with immediate-release formulations, and they include controlled-release, sustained-release, and prolonged-release formulations. These formulations minimize blood concentration fluctuations, reduce peak-related side effects, reduce dosing frequency, and improve patient compliance. A variety of products use different pharmaceutical strategies, including dissolution control (encapsulation or matrix; Feosol), diffusion control (membrane or matrix; Plendil ER), erosion (Sinemet CR), osmotic pump systems (Procardia XL, Glucotrol XL), and ion exchange resins (MS Contin suspension). Overdoses with modified-release formulations often result in a prolonged absorption phase, a delay to peak concentrations, and a prolonged duration of effect.7 Some delayed-release preparations are enteric coated and specifically designed to bypass the stomach and to release drug in the small intestine. Other delayed-release formulations (eg, Verelan PM) are designed to release the drug later but not specifically designed to bypass release in the stomach. Enteric-coated (acetylsalicylic acid {ASA}, divalproex sodium) formulations resist disintegration and delay the time to onset of effect.6 Dissolution is affected by ionization, solubility, and the partition coefficient. In the overdose setting, the formation of poorly soluble or adherent masses such as concretions of foreign material termed bezoars significantly delay the time to onset of toxicity (Table 9–2).4,11,29,30,60
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Most ingested xenobiotics are primarily absorbed in the small intestine as a result of the large surface area and extensive blood flow of the small intestines.59 Critically ill patients who are hypotensive, have a reduced cardiac output, or are receiving vasopressors such as norepinephrine have a decreased perfusion of vital organs, including the GI tract, kidneys, and liver.3 Not only is absorption delayed, but elimination is also diminished.57 Total GI transit time can be from 0.4 to 5 days, and small intestinal transit time is usually 3 to 4 hours. Extremely short GI transit times reduce absorption. This change in transit time is the unproven rationale for use of whole-bowel irrigation (WBI). Delays in emptying of the stomach impair absorption as a result of the delay in delivery to the small intestine. Delays in gastric emptying occur as a result of the presence of food, especially fatty meals; agents with anticholinergic, opioid, or antiserotonergic properties; ethanol; and any xenobiotic that results in pylorospasm (salicylates, iron).
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Bioavailability is a measure of the amount of xenobiotic that reaches the systemic circulation unchanged (Equation 9–5).38 The fractional absorption (F) of a xenobiotic is defined by the area under the plasma drug concentration versus time curve (AUC) of the designated route of absorption compared with the AUC of the IV route. The AUC for each route represents the amount absorbed.
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Gastric emptying and activated charcoal are used to decrease the bioavailability of ingested xenobiotics. The oral administration of certain chelators (deferoxamine, d-penicillamine) actually enhances the bioavailability of the complexed xenobiotic. The net effect of some chelators, such as succimer, is a reduction in body burden via enhanced urinary elimination even though absorption is enhanced.31
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Presystemic metabolism may decrease or increase the bioavailability of a xenobiotic or a metabolite.53 The GI tract contains microbial organisms that can metabolize or degrade xenobiotics such as digoxin and oral contraceptives and enzymes, such as peptidases, that metabolize insulin.54 However, in rare cases, GI hydrolysis can convert a xenobiotic into a toxic metabolite, as occurs when amygdalin is enzymatically hydrolyzed to produce cyanide, a metabolic step that does not occur when amygdalin is administered intravenously.27 Xenobiotic metabolizing enzymes and influx and efflux transporters such as organic anion transporting polypeptides (OATP) and P-glycoprotein (P-gp), respectively, may also affect bioavailability. Xenobiotic-metabolizing enzymes are found in the lumen of the small intestine and can substantially decrease the absorption of a xenobiotic.44,73 Some of the xenobiotic that enters the cell can then be removed by the P-gp transporter from the cell and returned to the GI lumen and reexposed to the metabolizing enzymes.44,73 Venous drainage from the stomach and intestines delivers orally (and intraperitoneally) administered xenobiotics to the liver via the portal vein and avoids direct delivery to the systemic circulation. This venous drainage allows hepatic metabolism to occur before the xenobiotic reaches the blood, and as previously mentioned, is referred to as the first-pass effect.2,76 The hepatic extraction ratio is the percentage of xenobiotic metabolized in one pass of blood through the liver.47 Xenobiotics that undergo significant first-pass metabolism (eg, propranolol, verapamil) are used at much lower IV doses than oral doses. Some drugs, such as lidocaine and nitroglycerin, are not administered by the oral route because of significant first-pass effect.4 Instead, sublingual, transcutaneous (topical), and rectal administration of drugs are used to bypass the portal circulation and avoid first-pass metabolism.
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In the overdose setting, presystemic metabolism may be saturated, leading to an increased bioavailability of xenobiotics such as cyclic antidepressants, phenothiazines, opioids, and many β-adrenergic antagonists.56 Hepatic metabolism usually transforms the xenobiotic into a less active metabolite but occasionally results in the formation of a more toxic xenobiotic such as occurs with the transformation of parathion to paraoxon.51 Biliary excretion into the small intestine usually occurs for these transformed xenobiotics of molecular weights greater than 350 Da and may result in a xenobiotic appearing in the feces even though it had not been administered orally.34,54,67 Hepatic conjugated metabolites such as glucuronides may be hydrolyzed in the intestines to the parent form or to another active metabolite that can be reabsorbed by the enterohepatic circulation.41,49,52,54 The enterohepatic circulation may be responsible for what is termed a double-peak phenomenon after the administration of certain xenobiotics.64 The double-peak phenomenon is characterized as a serum concentration that decreases and then increases again as xenobiotic is reabsorbed from the GI tract. Other causes include variability in stomach emptying, presence of food, or failure of a tablet dosage form.64