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Absorption and Distribution Absorption

In daily practice, it is the oral ingestion that is the predominant form ofapplication and is, therefore, discussed in more detail here. Several factors determine in sequence the speed and extent of absorption, and systemic bioavailability of aspirin after oral administration. The first is the solubility of the compound in aqueous media that is mainly determined by physicochemical properties of aspirin (Section 1.2.2), the kind of formulation, and the pH of the solvent. The second is the speed of passage through the stomach. This determines the contact time with the stomach mucosa and can vary considerably depending on the stomach filling state. The retention time in the stomach lumen is also important for side effects, that is, GI intolerance, and determines the passage time to reach the most significant absorption area - the mucosa of the small intestine.

Solubility of Aspirin in Aqueous Media The classical and first variable for action of any drug is its solubility in the (aqueous) medium of interest: corpora non agunt nisi soluta. Dissolution of a conventional aspirin tablet by 50% in 0.1 N HCl in a stirred sample in vitro under standard conditions is quite long and requires 30-60 min. This suggests a poor solubility of the drug at the acidic conditions of stomach juice. The stability of the compound is inversely related to pH and has a maximum at pH 2.5 ([1]; Section 1.2.1). Thus, the acidic pH in the stomach favors the stability of aspirin and prevents hydrolysis. However, it also largely prevents dissolution. Both factors contribute to the poor gastric tolerance of plain aspirin (Section 3.2.1). In the case of ingestion ofhigh (toxic) doses of aspirin, absorption can be additionally retarded and reduced by the formation of concretions (insoluble aggregates), facilitated by the poor solubility of the drug under these conditions. Standard doses of300 mg aspirin will result in millimolar concentrations of the compound in 50-100 ml gastric juice (Section 3.2.1).

Absorption in the Stomach The data about the extent of absorption of aspirin within the stomach are variable. According to Cooke and Hunt [2], about 10% of a predissolved 250 mg dose of aspirin is absorbed from an acid solution in the stomach though the main absorption site is the upper intestine. This is partially because of not only the already mentioned poor solubility of the compound at strong acidic pH but also the comparably small

0 20 40 60 min

Figure 2.1 Plasma total salicylate concentrations in healthy volunteers after oral intake of aspirin in various galenic formulations on an empty stomach. All preparations contained 640 mg of acetylsalicylic acid (modified after [4]).

absorption surface of the stomach mucosa: 0.2-0.3 m2 as opposed to the 100-200 m2 surface of the small intestine. The use of buffered aspirin preparations further reduces the small absorption in the stomach because ofan increased proportion of the ionized form [2]. Thus, buffer capacity of the aspirin formulation and its maintenance over time are important variables for gastric tolerance. On the contrary, use ofpredissolved preparations or water-soluble sodium salts will improve absorption and increase systemic bioavailability [3], though the use of buffered preparations has little effect on these parameters [4] (Figure 2.1).

Similar findings were obtained in rats. Though not all investigators could confirm this finding [6], social drinkers should be made aware of the possibility that aspirin may potentiate the effects of alcohol consumed postprandial [7].

The extent and velocity of absorption of aspirin from the stomach are also influenced by the speed of stomach emptying. Addition of antacids or buffering of stomach juice stimulates gastric emptying. This increases initially the plasma levels of aspirin and salicylate. Delayed gastric emptying, for example, by proton-pump inhibitors or atropine, has the opposite effect. In this respect, it is interesting to note that plasma salicylate levels in patients, who underwent total gastrectomy (Billroth II), were not significantly different from those in healthy controls after oral aspirin intake. All important pharmacokinetic variables (absorption kinetics, plasma halflife, elimination kinetics) were also unchanged [8].

Only the nondissociated, lipophilic aspirin can penetrate into the epithelial cells of the stomach mucosa [9]. According to a pKa of 3.5 for aspirin, 95% of the substance are not dissociated at a pH of 2 in the stomach lumen and, therefore, might exert direct erosive actions on the mucosa epithelial cells [2, 9, 10] (Section 3.2.1).

Though the absorption of aspirin in the stomach is small, it can, nevertheless, have important functional consequences, most important a potentiation of bleeding in connection with alcohol (Section 3.2.1).

Human gastric mucosal epithelial cells have a significant alcohol dehydrogenase activity that oxidizes alcohol and is inhibited by aspirin in a noncompetitive way [5]. Intake of 1 g oral aspirin results in a significant increase, by about 15%, of systemic bioavailability of alcohol in blood. No such effect is obtained after i.v. administration of alcohol, suggesting that it is not due to an inhibition - by aspirin - of alcohol metabolism by the liver. Interestingly, this effect is seen only in men but not in women, possibly due to the low or even absence of first pass metabolism of alcohol in the female stomach.

The pKa for aspirin is 3.5. This means that 50% of the compound is ionized at this pH and almost all of it at pH 6, that is, it is negatively charged within the stomach lumen. In this ionized form, the molecules are lipid insoluble and can (theoretically) penetrate cell membranes only via special channels. At pH levels below 3.5, the majorityofaspirin molecules are nondissociated,that is, lipid soluble and can penetrate cell membranes independent of specialized channels.

Orally taken aspirin exists in the acid stomach lumen primarily in the nonionized form. However, the totally dissolved amount is very small because of the poor solubility of the compound. After diffusion into the superficial stomach mucosal cells, there is a dissociation of aspirin within these cells: pH 7 versus pH 2, equivalent to an ionic gradient of 105 (!). This prevents rediffusion of salicylates into the stomach lumen ("ionic trap") and results in an intracellular (intramucosal) accumulation of aspirin and subsequent cytotoxic effects on mucosal cells. Similar considerations apply to salicylate with a pKa value of 3.0 (Figure 2.2).

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Stomach mucosa Stomach lumen

Figure 2.2 Local accumulation of salicylate (pKa = 3.0) in the stomach mucosa: ion trapping hypothesis (for further explanation, see the text).

Stomach mucosa Stomach lumen

Figure 2.2 Local accumulation of salicylate (pKa = 3.0) in the stomach mucosa: ion trapping hypothesis (for further explanation, see the text).

A pH-dependent kinetics of absorption and distribution is relevant not only for the stomach but also for local accumulation of salicylates at sites of inflammation with acidic pH. Similar considerations apply to the acceleration of urinary salicylate excretion after aspirin overdosing by alkalinization of urine (Section 3.1.1).

Taken together - not only because of pharmacodynamic actions of aspirin (Section 3.2.1) but also for pharmacokinetic reasons - the stomach is not required for aspirin absorption and is entirely a site of salicylate-related side effects.

Absorption in the Intestine Like most other drugs, aspirin is mainly absorbed in the upper intestine by passive diffusion of the nonionized form. The pH in the upper duodenum is about 2-4 and then increases gradually to about 7-8 in the distal small intestine and colon. The much larger surface of the (small) intestine, amountingto 100-200 m2, as well as the improved solubility of aspirin with increasing pH result in an increase ofthe totally absorbed amount as a net response, despite the higher degree of dissociation.

Absorption from Other Application Sites Cutaneous administration of salicylates in the form of ointments as an external medication is well known. This stimulated the idea ofpercutaneous administration of aspirin for systemic application after a significant absorption of salicylates had been shown [11]. Percutaneous application will improve gastric tolerance by avoiding the gastrointestinal passage. This might be useful in patients at an elevated risk for gastrointestinal bleeding or toxicity. In addition, the antiplatelet effects of aspirin might be enhanced by using skin patches as a drug reservoir from which the compound is slowly released. Avoiding high peak levels might additionally result in less inhibition of vascular prostacyclin production.

Cutaneous aspirin (750mg/day) was reported to inhibit serum thromboxane formation by 95 ± 3% in a small group (6) of healthy volunteers without inhibition of basal or bradykinin-stimulated vascular prostacyclin production [12]. However, a more systematic follow-up study in a larger group of volunteers [10] indicated that this approach may not always work as suggested. In this study, aspirin at the same cutaneous dose (750mg/day to 29 volunteers for 10 days) had a systemic bioavailability of only 4-8% and did reduce serum thromboxane by only <90%, which is probably of borderline clinical significance.

It was also shown that aspirin applied by skin patches undergoes rapid hydrolysis to salicy-late [13], thus eliminating the antiplatelet activity. However, cutaneous aspirin also reduced the pros-taglandin content of the gastroduodenal mucosal and caused mucosal injury. Thus, cutaneous aspirin has no advantages in comparison with other forms of application for systemic use.

Bioavailability Aspirin, applied as a (predissolved) standard oral single dose (600 mg), is essentially completely absorbed in the GI tract. There is an appreciable "first-pass" metabolism of aspirin to salicylate during intestinal uptake and liver passage. Thus, the duration of passage through the intestine, that is, the duration of exposition of aspirin to esterases of the intestinal wall and the presystemic circulation (Section 2.1.2), are critical for systemic bioavailability of the uncleaved compound. These factors do not play any role for the bioavailability of the primary metabolite salicylic acid. The deacetyla-tion follows a dose-independent, zero-order kinetics and reduces the systemic bioavailability of standard plain aspirin to about 50% at clinically relevant doses between 40 and 1300 mg [14-17]. The esterases that catalyze this reaction are nonspecific and are located in the intestinal mucosa, blood of the portal vein (red cells, platelets, plasma), and liver parenchyma.

The first-pass effect is less relevant for the antiinflammatory actions of salicylates because in this indication aspirin and salicylate are about equipo-tent. For acetylation reactions, such as inhibition of platelet function and, perhaps, generation of 15-hydroxy-eicosatetraenoic acid (15-(R)-HETE) by acetylation of COX-2, it is highly relevant. During presystemic circulation, platelets will be exposed to the total absorbed amount ofaspirin in portal vein blood whereas the organs in the systemic circulation, including vessel walls and gut will be exposed to only about 50% of total administered aspirin (Figure 2.3). Theoretically, even complete inhibition of the platelet cyclooxygenase will not require any circulating aspirin in the systemic circulation [18]. This will reduce systemic side effects and improve compliance, specifically during long-term prophylactic use.

These data are valid for standard preparations of plain aspirin but not for formulations with delayed release. The high potency and abundance of aspirin esterases in the intestinal mucosa and presystemic circulation allow for sustained hydrolysis of slow-release aspirin formulations during the prolonged GI passage time. Consequently, the systemic bioavailability of unchanged aspirin is markedly reduced [18, 19] whereas the bioavailability of salicylic acid remains unchanged [20, 21].

A 75 mg "slow-release" aspirin formulation was designed to take advantage from this particular pharma-cokinetics for cardiocoronary prophylaxis. The intention was to obtain selective inhibition of platelet COX-1 in the presystemic circulation but not the inhibition of prostacyclin in the systemic circulation because the levels of unmetabolized aspirin were too low in the systemic circulation to block vascular prostaglandin production. With this particular preparation, the Cmax of aspirin was 15-fold lower than that for a standard formulation with the same dose [22]. This hypothesis worked in a proof of concept study [23] but was never introduced clinically.

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Figure 2.3 Systemic bioavailability of aspirin after oral administration. After oral administration (100%), the majority (>80%) of aspirin enters unchanged the upper intestine. Aspirin passes the intestinal wall and enters the portal vein blood. In this presystemic circulation, about 50% of standard aspirin are deacetylated to salicylic acid. The remaining 45-50% of aspirin enter the systemic circulation via the liver and act on organs and the vessel wall. These conversion rates of aspirin refer to standard plain, uncoated preparations, and standard doses. Slow-release formulations will undergo a significantly greater presystemic deacetylation because of the prolonged passage time through the intestine. In all cases the deacetylated aspirin is converted 1: 1 to salicylic acid, that is, the bioavailability of salicylate is not affected by the deacetylation procedure.


Figure 2.3 Systemic bioavailability of aspirin after oral administration. After oral administration (100%), the majority (>80%) of aspirin enters unchanged the upper intestine. Aspirin passes the intestinal wall and enters the portal vein blood. In this presystemic circulation, about 50% of standard aspirin are deacetylated to salicylic acid. The remaining 45-50% of aspirin enter the systemic circulation via the liver and act on organs and the vessel wall. These conversion rates of aspirin refer to standard plain, uncoated preparations, and standard doses. Slow-release formulations will undergo a significantly greater presystemic deacetylation because of the prolonged passage time through the intestine. In all cases the deacetylated aspirin is converted 1: 1 to salicylic acid, that is, the bioavailability of salicylate is not affected by the deacetylation procedure. Particular Aspirin Formulations

Several galenic preparations have been developed to improve the pharmacokinetics of the compound and to reduce gastric side effects. These include buffered (i.e., easily soluble or predissolved) formulations and enteric-coated forms. Another option is i.v. administration of aspirin as water-soluble lysine salt or administration as sodium salt. Intravenous administration is preferentially used to obtain rapidly effective plasma levels of undegraded aspirin, for example, as a first measure in the treatment of acute coronary syndromes. Alternatively, effervescent formulations have been developed for rapid absorption and early start of action. These formulations are valuable galenic improvements above the poorly soluble plain standard preparation (Figure 2.1).

Buccal The administration of aspirin as a chewing tablet allows for buccal absorption, that is, a direct, rapid access of the active compound to the systemic circulation, avoiding first-step metabolism by the liver. This approach is thought to be particularly useful in the treatment of headache.

Intravenous Animal experiments suggested that i.v. aspirin did not cause gastric injury despite of nearly complete inhibition of serum thromboxane formation [24]. In clinical use, no overt signs of mucosal injury (microbleedings, gastric potential differences) did occur after i.v. application of aspirin, possibly because of avoidance of direct contacts of the (undissolved) substance with the stomach mucosa (Section 3.2.1). Intravenous aspirin (250-500 mg) is a widely used first-line measure to obtain fast inhibition of platelet function in acute coronary syndromes.

Buffered In one of the first systematic studies on the influence of galenics on aspirin plasma levels and GI blood loss, Stubbe et al. [25] found an apparently complete disappearance of occult blood from stool with an appropriately buffered aspirin preparation (Alka-Seltzer). In addition, peak plasma levels of salicylate were obtained earlier and were higher than after plain preparations [25]. This was assumed to be due to faster emptying of the drug into the intestine, and improved solubility.

Erosions of the stomach mucosa, occasionally seen with buffered plain aspirin, are probably due to a disturbed passage ("concretions") of large tablets and not due to direct mucosal injury [26]. On the contrary, buffering may shorten the half-life of action because of a more rapid renal excretion due to the alkaline pH [3, 26].

Enteric Coated Historically the first and most promising approach to improve gastric tolerance of aspirin was the introduction of enteric-coated formulations. The theoretical considerations to introduce this formulation were the insignificant (10%) absorption of aspirin in the stomach and the large body of evidence that gastric injury by aspirin requires direct contact of the active compound with the stomach mucosa. Enteric-coated formulations are resistant against stomach juice. This will avoid any physical interaction ofthe drug with the stomach mucosa, allowing for the release of the active drug only into the upper intestine. This is the major site of salicylate absorption at a markedly improved solubility because of the more alkaline pH. Distribution

Similar to absorption, distribution of salicylates within body fluids and tissues is determined mainly by pH-dependent passive diffusion of the unbound fraction. As already seen with the stomach, there is a balance between the free, nondissociated acid at both sites of the cell membrane. Any decrease in pH, for example, during acute salicylate intoxication, enhances the accumulation of the substance in the tissue and increases the symptoms of poisoning (Section 3.1.1).

Dose Dependency of the Distribution Volume The apparent distribution volume of salicylates is dose dependent. At low therapeutic doses it amounts to about 0.2 l/kg. This is equivalent to a predominant distribution in the extracellular space because of high (80-95%) binding to plasma albumin [27].

Protein binding of aspirin and salicylate occurs via the phenolic hydroxyl group of the substances [28,29]. Athigh (anti-inflammatory) doses or salicy-late poisoning, the apparent distribution volume increases to about 0.5 l/kg. This is because of a saturation ofsalicylate binding to plasma proteins, subsequent diffusion into the intracellular space, and binding to tissue proteins. In addition, some metabolizing enzymes also become saturated (Section 2.1.2). An increase of the volume of distribution and reduced binding to plasma proteins also probably explain the prolonged bleeding time after aspirin in uremic patients [30] and the overproportional high levels of free salicylate after high-dosage aspirin treatment, for example, in children with Kawasaki's disease (Section 4.3.2). It is possible that the intracellular accumulation of (free) salicylic acid that has to be expected at high anti-inflammatory doses is a precondition for its pharmacological efficacy. High tissue levels of salicy-lates might be a requirement for not only the inhibition of cytokine or tumor promoter-induced gene expression, including transcriptional COX-2 regulation (Section 2.2.2) but also non-COX-related effects, for example, on cell energy metabolism (Section 2.2.3).

Salicylate Levels in Plasma The plasma salicylate levels differ markedly, depending on the dose and the distribution equilibrium, including the protein (albumin) content. At low antiplatelet doses essentially all salicylate is albumin bound. However, this is not relevant for the antiplatelet effects of the compound since these effects are entirely due to the acetylation potential and independent ofsalicy-late. At analgesic single doses of 0.6-1 g, mean salicylate plasma levels of about 30 mg/ml and aspirin levels of 3 mg/ml are obtained. The protein binding (ultrafiltration) of a 600 mg single oral dose amounts to 82 and 58% for salicylate and aspirin, respectively [31]. The level of analgesia appears to correlate well with the salicylate plasma level [32]. Thus, at these concentrations, 10% of total salicylate is free, that is, able to move out from plasma into cells and tissues. This percentage of free salicylate at inflammatory daily doses of about 5 g, equivalent to total plasma levels of 300 mg/ml and more (1-3 mM) amounts to about 10% and to 30% at toxic doses (Table 2.1). Thus, higher doses of aspirin result not only in higher levels of total plasma salicylate but additionally also in a marked increase of the unbound fraction [33, 34].

Salicylate Levels in Selected Tissues and Body Fluids

The maximum tissue levels of salicylates in the synovial fluid amount to about 50% of plasma level [35]. Salicylate concentrations in the cerebrospinal fluid are about 10-25% of the plasma level, and there is no tight correlation to the plasma level [36]. Similar low percentages of plasma level, about 30%, are found in the perilymph. In contrast, salicylate levels in the fetal circulation are only slightly lower than in the maternal circulation [37]. This is particularly relevant for newborn prior to

Table 2.1 Plasma salicylate levels and percentage of free salicylate in dependency on dosing (modified after [33]).

Max. plasma salicylate (mM)

mg/kg Free

Clinical use ASA dose (70 kg BW) Total Free salicylate

Antiplatelet 100 mg/day (maintenance dose) <2 <0.1 a

Analgesic 1 g single dose 15 0.5 0.005 1%

Anti-inflammatory 6-8g/day 100 1.5-2.5 0.15-0.60 10%

Toxic 30g single dose and more >400 3.0-10.0 1.0-5.0 30%

^Irrelevant since clinical efficacy depends on acetylation and is independent of salicylate.

delivery whose renal and hepatic clearance systems are not yet fully developed (see Section 3.1.2). Modifying Factors

Food Intake The compliance for regular intake of drugs is improved if this is coupled with food intake. This is particularly valid for patients at older age and the intake of drugs that might irritate the stomach, such as aspirin. However, simultaneous eating might prolong the passage time through the stomach, allow for adsorption of the drug to food particles and allow a reduced velocity of absorption in the small intestine [38].

Aspirin is not recommended to be taken on an empty stomach. The reason is that the substance is a stronger irritant for the mucosa in the empty state and will also stay there for a longer period of time. In addition, absorption occurs predominantly in the upper small intestine and is independent of the stomach filling state. However, the absorption of aspirin is quantitatively optimal if the drug is ingested in a relatively large volume of water on an empty stomach [39].

Ferner and colleagues compared the plasma levels of aspirin and salicylate after oral intake of 1200 mg standard aspirin in healthy volunteers either starved for 37 h or after having a standard breakfast. The maximum plasma levels of aspirin were 17 ± 3 mg/ml at 22 min in starved and 24± 4mg/ml in nonstarved persons. The maximum salicylate plasma levels were 57 ± 7 mg/ml in starved and 65 ±8mg/ml in nonstarved subjects. None ofthese differences were significant. There were also no differences in the pharmacodynamics of aspirin as measured in terms of metabolic parameters. The conclusion was that eating, that is, the filling state of the stomach, does affect neither the bioavailability nor the efficacy ofstandard aspirin and salicylic acid [40].

It has, however, to be considered that delayed gastric emptying or prolonged passage through the intestine will also prolong the exposure time of aspirin against hydrolyzing enzymes. This, eventually results in a reduced systemic bioavailability of aspirin (Section 2.1.2) whereas the bioavailability of salicylic acid remains unchanged. Similar data were published with controlled-release formulations [22]. However, marked delays in the absorption of aspirin from enteric-coated tablets may be observed when they are consumed with food. This effect appears to be particularly pronounced in women [41]. Finally, the delayed and prolonged absorption ofaspirin from enteric-coated formulations has to be considered in the treatment of salicylate poisoning (Section 3.1.1).

Vegetables as a Natural Source of Salicylates Many fruits and vegetables contain different forms of salicylates, in particular, the salicylic acid ester salicin. These salicylates or metabolites thereof might circulate in plasma. Their level might be increased by an appropriate (vegetarian) diet and, eventually, add to the therapeutic benefit of exogenous aspirin. There is mixed information, whether clinically relevant amounts of salicylates can be obtained in plasma after intake of salicylate-rich diets [42, 43]. One recent study has, however, shown that the low circulating salicylate levels in plasma [43] can be significantly, though not impressively, increased by a vegetarian diet [44] (Figure 2.4). This has been taken as evidence to explain beneficial effects of certain vegetables in chemoprevention of colorectal carcinoma and is discussed in detail elsewhere (Section 4.3.1). Al io : 8 6 4

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