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Aspirin: Plasma concentration and effects
THROMBOSIS RESEARCH,Supplement TV: 105-111, 1983 0049-3848183 $3.00 + .OO Printed in the USA. Copyright (c) 1983 Pergamon Press Ltd. All rights
ASPIRIN: Faculty
reserved.
PLASMACONCENTRATION AND EFFECTS J. J. Thiessen of Pharmacy, University of Toronto Toronto, Canada M5S 1Al
ABSTRACT The antithrombotic effect of acetylsalicylic acid is intimately linked to its reactivity. The labile acetyl moiety irreversibly acetylates not only cycle-oxygenase, other biological but components. The presence of ubiquitous esterases leads to the rapid disappearance of ASA from the body. The pharmacokinetics of ASA is affected by the dosage form used and the presence of food. Despite the absence of a definable relationship between plasma ASA levels and response, recent data would suggest a dose of about 0.5 mg/kg/day adequately suppresses platelet aggregation without affecting prostacyclin formation. INTRODUCTION Acetylsalicylic acid (aspirin, ASA) is a drug whose history and annual consumption undoubtedly identifies it as the most widely known and consnonly used drug in the world. The comparatively recent finding that it disrupts prostaglandin formation has served to explain the origin of many of its effects. In order to appreciate more fully the relationship between the administered ASA dose and the observed antithrombotic effects, it is important to understand the chemical nature of the molecule and its rapid disappearance from the body after ingestion. Reactivity of ASA. 1) is a weak acid with a pKa of 3.5 and ASA (Fig. therefore at physiological pH, 99.99% is present as the anion. It is readily hyrdolyzed to salicylic acid (SA, Fig. 1) not only in tablets under normal storage conditions, but also in vivo. Edwards (l), investigating its aqueous hydrolysis at 17’C, found ASA to be most stable near pH 2.5. Acid- and base-catalyzed hydrolysis of ASA can be explained by rather standard reaction mechanisms. The latter process, involving nucleophilic attack by OH’, provides a model for the acetylation of biological substrates in the body (Fig. 2). When aspirin is administered to the body, it is hydrolyzed by ubiquitous, per haps non-specific esterases in many tissues. Although cycle-oxygenase acetylation by ASA has drawn considerable attention, the acetyiated protein might simply be considered another esterase.
Key
words:
Acetylsalicylic plasma levels.
acid,
pharmacokinetics, 105
antithrombotic
response,
106
ASPIRIN
Suppl.
PHARMACOKINETICS
--EXCRETE3
HO GA
SAG
FIG.
1
The fate of acetylaalicylic acid in the body. The pathways identified by a star are saturable with therapeutic dosage regimen.
______-_--->
FIG.
to
HO
2
A scheme depicting base-catalyzed yield acetate and salicylate, of ASA by a protein resulting accompanied by the liberation
hydrolysis of ASA or nucleophilic attack in its acetylation of salicylate.
IV,
1983
Suppl.
Iv,
1983
ASPIRIN PHARMACOKINETICS
107
any site which becomes acetylated could be regarded as an esteratic In fact, The work of Hawkins et al (2) has demonstrated the acetylation by ASA site. such as albumin, globulins, enzymes and even of various endogenous proteins DNA. of The instability half-life is measured in (Table 1).
ASA becomes more apparent when its hydrolysis various biological or simulated biological fluids
TABLE 1 Half-life
Initial ASA Concentration (@ml)
Medium Krebs-Ringer Bicarbonate Human gastric Human duodenal
of ASA at 37’C (3,4)
(pH 7.4) juice juice
ASA Half-life
10
15.5
10
16
10
17
Human blood
13
0.5
Human plasma
13
1.9
(hr)
In a recent study examining why whole blood is more active than plasma, it has been shown that an inverse linear relationship exists between ASA half-life and hematocrit (5). The use of diisopropylfluorophosphate, an agent known to irreversibly inhibit red cell acetylcholinesterase, was also found to impede the hydrolysis rate. Thus acetylcholinesterase is implicated in ASA hydrolysis by the erythrocytes. Studies have also been conducted with sections of the gastrointestinal tract to assess how these tissues might hydrolyze ASA after its oral administration. The stomach of rabbits, while able to hydrolyze the drug, was only about l/3 as active as the duodenum, middle ileum and lower ileum Of the tissues examined in man, the mucosal cells (4). of the jejunum were found to possess the greatest esterase activity (6). These observations indicate that some of the orally administered ASA will be destroyed before it reaches the circulation. Pharmacokinetics of ASA. On the basis of the previous information it i s not surprising that the --in vivo administration of aspirin leads to its r apid disappearance from the body. Rowland and Riegelman (7) demonstrated that after giving 650 mg intravenously, plasma ASA concentrations exhibited a bi-exponential profile with a terminal half-life of about 15 min. Thi s information indicates that plasma ASA levels are virtually non-existent 90 min after intravenous aspirin. However, its hydrolysis product, SA, as well as the metabolic products of SA (Fig. 11, will be present in the body for an extended period of time. Although SA appears to be devoid of antithrombotic activity (8). increasing evidence suggests that it may interfere with the activity of ASA (9-li). It is therefore important to be knowledgeable about
.4SPIRXN PHARMACOKINETICS
108
SUPPl.
IV,
1983
the pharmacokinetics of SA, particularly concerning the roie of two elimination routes (the formation of salicyluric acid and the phenolic glucuronide) which may show signs of saturation with continuous ASA administration (12). Whether such issues are important in the use of ASA as an antithrombotic will be considered in the subsequent agent paper. Nevertheless, a comparison of the available salient pharmacokinetic parameters for ASA and SA are found in Table 2. TABLE 2 Mean Pharmacokinetic Parameters Obtained for ASA and SA After Administering 650 mg of Each Salicylate Intravenously (7). Pharmacokinetic
Parameter
Half-life
of distribution
Half-life
of eliminatin
phase (min) phase (min)
V,(L)
V&L) Total
body clearance
Unbound fraction
(ml/min)
in plasma
Salicylate ASA
-SA
2.7
3.8
14.9
238
6.6
5.5
11.3
9.4
680 - 0.7
27 - 0.9
The foregoing discussion has focused upon intravenously administered aspirin. ASA is however generally given orally and the available information indicates that the plasma acetylsalicylic acid profiles may vary considerably First, rapidly absorbed ASA tablets, whether under different conditions. buffered or unbuffered, will generaly exhibit terminal phase half-lives the maximum plasma levels similar to that reported in Table 2, although achieved will be lower than those for a comparable intravenous dose (4,131. The maximum level will usually be encountered within the first hour after tablet ingestion. Second, the presence of food may have a dramatic influence upon the levels obtained. Generally, food in the .gastrointestinal tract delays the appearance of ASA in the plasma and also serves to dampen the is ingested as enteric-coated tablets, the levels (14). Third, when aspirin appearance of ASA in plasma will be frequently be delayed and unpredictable. low and somewhat prolonged concentrations will be encountered which Also, reflect the rate-limiting properties of ASA absorption from such dosage forms It has been shown that some of these products may remain in the fundic (15). region of the stomach up to 7 hours or longer before they are passed into the Product 3 intestine where disintegration and dissolution takes place (16). using enteric-coated granules may avoid this problem (17) because these small particles will not be trapped in the fundus as readily. For many drugs a more reliable ASA and the Antithrombotic Response. The relationship has been found between plasma levels and response. preceding section has illustrated that the same ASA dose may give different Yet, no study has plasma levels depending upon how it is administered.
Suppl.
IV, 1983
ASPIRIN PHARMACOKINETI CS
109
carefully examined the relationship between ASA levels and the effect upon Indirectly, our laboratory has shown that a poor prostaglandin formation. are offered for such a (15). Two reasons relationship may be found since the response appears to be mediated via an conclusion. First, the length of total exposure of the enzyme may be more irreversible process, important because such exposure should reflect the extent of acetylation. Second, reports to date have shown that the response outlives the presence of ASA in the body, an expected finding if the turnover time of the enzyme does not match the disappearance time of ASA from the body. Thus, the use of ASA dose-response studies may have considerable validity until the kinetics of the response is fully defined. The use of different doses to evaluate the effects of ASA has been the focal point of much research activity and many of these studies have been In 1970, O’Brien and co-workers examined cited in a review by Moncada (18). the effect of single ASA doses (0.3 to 12.7 mg/kg) upon adrenalin-induced platelet aggregation. At a dose of 0.6 mg/kg, two of the 4 subjects studied hours after dose showed complete inhibition of aggregation l- l/2 administration. other investigators have Since these initial experiments, reached similar conclusions. For example, Patrignani et al (19) found serum TxB production to be essentially inhibited 24 hours following a single 100 mg i SA dose. The effect of ASA upon prostacyclin formation has been explored by various investigators in an attempt to find a dose which will block platelet aggregation and not inhibit vascular wall prostaglandin formation. For example, Hanley et al (20) have shown in 47 patients admitted for varicose veins, that 40 mg ASA did not alter venous vascular PG12 producton whereas this dose inhibited platelet aggregation. Recent data has also shown that daily ASA administration (0.45 mg/kg/day) leads to a cumulative effect upon platelets so that TxB production is virtually inhibited, but there is no effect upon urinary 6- z eto-PGF, Q suggesting no effect upon the formation of prostacyclin (19). CONCLUSIONS Although the pharmacokinetics of ASA has been firmly established, the pr eci se quantitative nature of its effects upon the various tissue prostaglandin systems remains to be defined. At the present time, a dose of about 0.5 mg/kg/day leads to adequate inhibition of platelet prostaglandin production without affecting a similar biochemical system in the blood vessel wall. REFERENCES 1.
EDWARDS, L. J. 723-735, 1950.
2.
HAWKINS,D., PINCKARD, R.N., and FARR, R.S. Acetylation of human serum albumin by acetylsalicylic acid. Science 160, 780-781, 1968.
3.
HARRIS, P.A., and REIGELMAN,S. Acetylsalicylic human blood and plasma. I. Methodology and _in vitro Sci. 56, 713-716, 1967.
The
hydrolysis
of
aspirin.
Trans.
Faraday
Sot.
46,
acid hydrolysis in studies. J. Pharm. --
110
ASPIRIN PHARMACOKINETICS
Suppl. IV, 1983
ROWLAND, M., RIEGELMAN, S., HARRIS, P.A., and SHOLKOFF, S.D. Absorption kinetics of aspirin in man following oral administration of an aqueous solution. J. Pharm. Sci. 61, 379-385, 1972. 5.
COSTELLO, P.B., and GREEN, F.A. Aspirin survival in human blood modulated by the concentration of erythrocytes. Arth. Rheum. 25, 550-555, 1982.
6.
DAWSON, I., and PRYSE-DAVIES, J. The distribution of certain enzyme systems in the normal gastrointestinal tract. Gastroenterology 44, 745-760, 1963.
7.
ROWLAND, M., and RIEGELMAN, S. Pharmacokinetics of acetylsalicylic acid and salicylic acid after intravenous administration in man. J. Pharm. Sci. 57, 1313-1319, 1968.
8.
WEISS, H.J., ALEDORT, L.M., and KOCHWA, S. The effect of salicylates on the hemostatic properties of platelets in man. J. Clin. Invest. 47, 2169-2180, 1968.
9.
Interference by sulfinpyrazone and ALI, M., and MCDONALD, J.W.D. salicylate of aspirin inhibition of platelet cycle-oxygenase activity. Prostaglandins Med. 3, 327-332, 1979.
10.
MERINO, J., LIVIO, M., RAJTAR, G., and DE GAETANO, G. Salicylate reverses in vitro aspirin inhibition of rat platelet and vascular prostaglanXn generation. Biochem. Pharmacol. 29, 1039-1096, 1980.
11.
DEJANO, C., CERLETTE, C., DE CASTELLARNAU, C., LIVIO, M., GALLETTI, F., LATINI, R., and DE GAETANO, G. Salicylate-aspirin interaction in the rat. J. Clin. Invest. 68, 1108-1112, 1981.
12.
LEVY, G., and TSUCHIYA, T. Salicylate accumulation kinetics in man. Engl. J. Med. 287, 430-432, 1972.
13.
LINNOILA, M., and LEHTOLA, J. Absorption, and effect on gastric mucosa, of buffered and non-buffered tablets of acetylsalicylic acid. Int. J. Clin. Pharmacol. 15, 61-64, 1977.
14.
KOCH, P.A., SCHULTZ, C.A., WILLIS, R.J., HALLQUIST, S.L., and WELLING, P.G. Influence of food and fluid ingestion on aspirin bioavailability. J. Pharm. Sci. 67, 1533-1535, 1978.
15.
THIESSEN, J.J., GRAD, H., MACLEOD, S.M., and SPINO, M. Human platelet response to three salicylate dosage forms. Biopharm. Drug. Disp., 1982 (in press).
16.
BLYTHE, R.H., GRASS, G-M., and MACDONALD, D.R. The formulation and evaluation of enteric coated aspirin tablets. Am. J. Pharmacol. 131, 206-216, 1959.
17.
BOGENTOFT, C., CARLSSON, T., EKENVED, S., and MAGNUSSON, A. Influence of food on the absorption of acetylsalicylic acid from enteric coated dosage forms. Eur. J. Clin. Pharmacol. 14, 351-355, 1978.
-N.
suppl. IV, 1983
ASPIRIN PHARMACOKINETICS
18. MONCADA, S. biological importanceof prostacyclin. Br. J. 76, 3-31, 1982. 19.
111
Pharmac.
PATRIGNANI, P., FILABOZZI, P., and PATRONO, C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J. Clin. Invest. 69, 1366-1372,1982.
20. HANLEY, S.P., BEVAN, J., COCKBILL, S.R., and HEPTINSTALL, S. Differentialinhibitionby low-doseaspirin of human venous prostacyclin synthesisand plateletthromboxanesynthesis. Lancet i, 969-971, 1981.
ASPIRIN: Faculty
reserved.
PLASMACONCENTRATION AND EFFECTS J. J. Thiessen of Pharmacy, University of Toronto Toronto, Canada M5S 1Al
ABSTRACT The antithrombotic effect of acetylsalicylic acid is intimately linked to its reactivity. The labile acetyl moiety irreversibly acetylates not only cycle-oxygenase, other biological but components. The presence of ubiquitous esterases leads to the rapid disappearance of ASA from the body. The pharmacokinetics of ASA is affected by the dosage form used and the presence of food. Despite the absence of a definable relationship between plasma ASA levels and response, recent data would suggest a dose of about 0.5 mg/kg/day adequately suppresses platelet aggregation without affecting prostacyclin formation. INTRODUCTION Acetylsalicylic acid (aspirin, ASA) is a drug whose history and annual consumption undoubtedly identifies it as the most widely known and consnonly used drug in the world. The comparatively recent finding that it disrupts prostaglandin formation has served to explain the origin of many of its effects. In order to appreciate more fully the relationship between the administered ASA dose and the observed antithrombotic effects, it is important to understand the chemical nature of the molecule and its rapid disappearance from the body after ingestion. Reactivity of ASA. 1) is a weak acid with a pKa of 3.5 and ASA (Fig. therefore at physiological pH, 99.99% is present as the anion. It is readily hyrdolyzed to salicylic acid (SA, Fig. 1) not only in tablets under normal storage conditions, but also in vivo. Edwards (l), investigating its aqueous hydrolysis at 17’C, found ASA to be most stable near pH 2.5. Acid- and base-catalyzed hydrolysis of ASA can be explained by rather standard reaction mechanisms. The latter process, involving nucleophilic attack by OH’, provides a model for the acetylation of biological substrates in the body (Fig. 2). When aspirin is administered to the body, it is hydrolyzed by ubiquitous, per haps non-specific esterases in many tissues. Although cycle-oxygenase acetylation by ASA has drawn considerable attention, the acetyiated protein might simply be considered another esterase.
Key
words:
Acetylsalicylic plasma levels.
acid,
pharmacokinetics, 105
antithrombotic
response,
106
ASPIRIN
Suppl.
PHARMACOKINETICS
--EXCRETE3
HO GA
SAG
FIG.
1
The fate of acetylaalicylic acid in the body. The pathways identified by a star are saturable with therapeutic dosage regimen.
______-_--->
FIG.
to
HO
2
A scheme depicting base-catalyzed yield acetate and salicylate, of ASA by a protein resulting accompanied by the liberation
hydrolysis of ASA or nucleophilic attack in its acetylation of salicylate.
IV,
1983
Suppl.
Iv,
1983
ASPIRIN PHARMACOKINETICS
107
any site which becomes acetylated could be regarded as an esteratic In fact, The work of Hawkins et al (2) has demonstrated the acetylation by ASA site. such as albumin, globulins, enzymes and even of various endogenous proteins DNA. of The instability half-life is measured in (Table 1).
ASA becomes more apparent when its hydrolysis various biological or simulated biological fluids
TABLE 1 Half-life
Initial ASA Concentration (@ml)
Medium Krebs-Ringer Bicarbonate Human gastric Human duodenal
of ASA at 37’C (3,4)
(pH 7.4) juice juice
ASA Half-life
10
15.5
10
16
10
17
Human blood
13
0.5
Human plasma
13
1.9
(hr)
In a recent study examining why whole blood is more active than plasma, it has been shown that an inverse linear relationship exists between ASA half-life and hematocrit (5). The use of diisopropylfluorophosphate, an agent known to irreversibly inhibit red cell acetylcholinesterase, was also found to impede the hydrolysis rate. Thus acetylcholinesterase is implicated in ASA hydrolysis by the erythrocytes. Studies have also been conducted with sections of the gastrointestinal tract to assess how these tissues might hydrolyze ASA after its oral administration. The stomach of rabbits, while able to hydrolyze the drug, was only about l/3 as active as the duodenum, middle ileum and lower ileum Of the tissues examined in man, the mucosal cells (4). of the jejunum were found to possess the greatest esterase activity (6). These observations indicate that some of the orally administered ASA will be destroyed before it reaches the circulation. Pharmacokinetics of ASA. On the basis of the previous information it i s not surprising that the --in vivo administration of aspirin leads to its r apid disappearance from the body. Rowland and Riegelman (7) demonstrated that after giving 650 mg intravenously, plasma ASA concentrations exhibited a bi-exponential profile with a terminal half-life of about 15 min. Thi s information indicates that plasma ASA levels are virtually non-existent 90 min after intravenous aspirin. However, its hydrolysis product, SA, as well as the metabolic products of SA (Fig. 11, will be present in the body for an extended period of time. Although SA appears to be devoid of antithrombotic activity (8). increasing evidence suggests that it may interfere with the activity of ASA (9-li). It is therefore important to be knowledgeable about
.4SPIRXN PHARMACOKINETICS
108
SUPPl.
IV,
1983
the pharmacokinetics of SA, particularly concerning the roie of two elimination routes (the formation of salicyluric acid and the phenolic glucuronide) which may show signs of saturation with continuous ASA administration (12). Whether such issues are important in the use of ASA as an antithrombotic will be considered in the subsequent agent paper. Nevertheless, a comparison of the available salient pharmacokinetic parameters for ASA and SA are found in Table 2. TABLE 2 Mean Pharmacokinetic Parameters Obtained for ASA and SA After Administering 650 mg of Each Salicylate Intravenously (7). Pharmacokinetic
Parameter
Half-life
of distribution
Half-life
of eliminatin
phase (min) phase (min)
V,(L)
V&L) Total
body clearance
Unbound fraction
(ml/min)
in plasma
Salicylate ASA
-SA
2.7
3.8
14.9
238
6.6
5.5
11.3
9.4
680 - 0.7
27 - 0.9
The foregoing discussion has focused upon intravenously administered aspirin. ASA is however generally given orally and the available information indicates that the plasma acetylsalicylic acid profiles may vary considerably First, rapidly absorbed ASA tablets, whether under different conditions. buffered or unbuffered, will generaly exhibit terminal phase half-lives the maximum plasma levels similar to that reported in Table 2, although achieved will be lower than those for a comparable intravenous dose (4,131. The maximum level will usually be encountered within the first hour after tablet ingestion. Second, the presence of food may have a dramatic influence upon the levels obtained. Generally, food in the .gastrointestinal tract delays the appearance of ASA in the plasma and also serves to dampen the is ingested as enteric-coated tablets, the levels (14). Third, when aspirin appearance of ASA in plasma will be frequently be delayed and unpredictable. low and somewhat prolonged concentrations will be encountered which Also, reflect the rate-limiting properties of ASA absorption from such dosage forms It has been shown that some of these products may remain in the fundic (15). region of the stomach up to 7 hours or longer before they are passed into the Product 3 intestine where disintegration and dissolution takes place (16). using enteric-coated granules may avoid this problem (17) because these small particles will not be trapped in the fundus as readily. For many drugs a more reliable ASA and the Antithrombotic Response. The relationship has been found between plasma levels and response. preceding section has illustrated that the same ASA dose may give different Yet, no study has plasma levels depending upon how it is administered.
Suppl.
IV, 1983
ASPIRIN PHARMACOKINETI CS
109
carefully examined the relationship between ASA levels and the effect upon Indirectly, our laboratory has shown that a poor prostaglandin formation. are offered for such a (15). Two reasons relationship may be found since the response appears to be mediated via an conclusion. First, the length of total exposure of the enzyme may be more irreversible process, important because such exposure should reflect the extent of acetylation. Second, reports to date have shown that the response outlives the presence of ASA in the body, an expected finding if the turnover time of the enzyme does not match the disappearance time of ASA from the body. Thus, the use of ASA dose-response studies may have considerable validity until the kinetics of the response is fully defined. The use of different doses to evaluate the effects of ASA has been the focal point of much research activity and many of these studies have been In 1970, O’Brien and co-workers examined cited in a review by Moncada (18). the effect of single ASA doses (0.3 to 12.7 mg/kg) upon adrenalin-induced platelet aggregation. At a dose of 0.6 mg/kg, two of the 4 subjects studied hours after dose showed complete inhibition of aggregation l- l/2 administration. other investigators have Since these initial experiments, reached similar conclusions. For example, Patrignani et al (19) found serum TxB production to be essentially inhibited 24 hours following a single 100 mg i SA dose. The effect of ASA upon prostacyclin formation has been explored by various investigators in an attempt to find a dose which will block platelet aggregation and not inhibit vascular wall prostaglandin formation. For example, Hanley et al (20) have shown in 47 patients admitted for varicose veins, that 40 mg ASA did not alter venous vascular PG12 producton whereas this dose inhibited platelet aggregation. Recent data has also shown that daily ASA administration (0.45 mg/kg/day) leads to a cumulative effect upon platelets so that TxB production is virtually inhibited, but there is no effect upon urinary 6- z eto-PGF, Q suggesting no effect upon the formation of prostacyclin (19). CONCLUSIONS Although the pharmacokinetics of ASA has been firmly established, the pr eci se quantitative nature of its effects upon the various tissue prostaglandin systems remains to be defined. At the present time, a dose of about 0.5 mg/kg/day leads to adequate inhibition of platelet prostaglandin production without affecting a similar biochemical system in the blood vessel wall. REFERENCES 1.
EDWARDS, L. J. 723-735, 1950.
2.
HAWKINS,D., PINCKARD, R.N., and FARR, R.S. Acetylation of human serum albumin by acetylsalicylic acid. Science 160, 780-781, 1968.
3.
HARRIS, P.A., and REIGELMAN,S. Acetylsalicylic human blood and plasma. I. Methodology and _in vitro Sci. 56, 713-716, 1967.
The
hydrolysis
of
aspirin.
Trans.
Faraday
Sot.
46,
acid hydrolysis in studies. J. Pharm. --
110
ASPIRIN PHARMACOKINETICS
Suppl. IV, 1983
ROWLAND, M., RIEGELMAN, S., HARRIS, P.A., and SHOLKOFF, S.D. Absorption kinetics of aspirin in man following oral administration of an aqueous solution. J. Pharm. Sci. 61, 379-385, 1972. 5.
COSTELLO, P.B., and GREEN, F.A. Aspirin survival in human blood modulated by the concentration of erythrocytes. Arth. Rheum. 25, 550-555, 1982.
6.
DAWSON, I., and PRYSE-DAVIES, J. The distribution of certain enzyme systems in the normal gastrointestinal tract. Gastroenterology 44, 745-760, 1963.
7.
ROWLAND, M., and RIEGELMAN, S. Pharmacokinetics of acetylsalicylic acid and salicylic acid after intravenous administration in man. J. Pharm. Sci. 57, 1313-1319, 1968.
8.
WEISS, H.J., ALEDORT, L.M., and KOCHWA, S. The effect of salicylates on the hemostatic properties of platelets in man. J. Clin. Invest. 47, 2169-2180, 1968.
9.
Interference by sulfinpyrazone and ALI, M., and MCDONALD, J.W.D. salicylate of aspirin inhibition of platelet cycle-oxygenase activity. Prostaglandins Med. 3, 327-332, 1979.
10.
MERINO, J., LIVIO, M., RAJTAR, G., and DE GAETANO, G. Salicylate reverses in vitro aspirin inhibition of rat platelet and vascular prostaglanXn generation. Biochem. Pharmacol. 29, 1039-1096, 1980.
11.
DEJANO, C., CERLETTE, C., DE CASTELLARNAU, C., LIVIO, M., GALLETTI, F., LATINI, R., and DE GAETANO, G. Salicylate-aspirin interaction in the rat. J. Clin. Invest. 68, 1108-1112, 1981.
12.
LEVY, G., and TSUCHIYA, T. Salicylate accumulation kinetics in man. Engl. J. Med. 287, 430-432, 1972.
13.
LINNOILA, M., and LEHTOLA, J. Absorption, and effect on gastric mucosa, of buffered and non-buffered tablets of acetylsalicylic acid. Int. J. Clin. Pharmacol. 15, 61-64, 1977.
14.
KOCH, P.A., SCHULTZ, C.A., WILLIS, R.J., HALLQUIST, S.L., and WELLING, P.G. Influence of food and fluid ingestion on aspirin bioavailability. J. Pharm. Sci. 67, 1533-1535, 1978.
15.
THIESSEN, J.J., GRAD, H., MACLEOD, S.M., and SPINO, M. Human platelet response to three salicylate dosage forms. Biopharm. Drug. Disp., 1982 (in press).
16.
BLYTHE, R.H., GRASS, G-M., and MACDONALD, D.R. The formulation and evaluation of enteric coated aspirin tablets. Am. J. Pharmacol. 131, 206-216, 1959.
17.
BOGENTOFT, C., CARLSSON, T., EKENVED, S., and MAGNUSSON, A. Influence of food on the absorption of acetylsalicylic acid from enteric coated dosage forms. Eur. J. Clin. Pharmacol. 14, 351-355, 1978.
-N.
suppl. IV, 1983
ASPIRIN PHARMACOKINETICS
18. MONCADA, S. biological importanceof prostacyclin. Br. J. 76, 3-31, 1982. 19.
111
Pharmac.
PATRIGNANI, P., FILABOZZI, P., and PATRONO, C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J. Clin. Invest. 69, 1366-1372,1982.
20. HANLEY, S.P., BEVAN, J., COCKBILL, S.R., and HEPTINSTALL, S. Differentialinhibitionby low-doseaspirin of human venous prostacyclin synthesisand plateletthromboxanesynthesis. Lancet i, 969-971, 1981.