Gastric coated aspirin retention by Salah EL MOUSTAGHFIR

J. vet. Pharmacol. Therap. 13,148-153, 1990.

Gastric retention of enteric-coated aspirin tablets in beagle dogs R. C. NAP, D. J. BREEN, T. J. G. M. LAM & J . J. DE BRUYNE Department of Clinical Sciences of Companion Animals Utrecht University, PO BOX80.154. 3508 TD, Utrecht, the Netherlands Nap, R.C., Breen, D.J., Lam, T.J.G.M. & d e Bruyne, J.J. Gastric retention of enteric-coated aspirin tablets in beagle dogs. J . vel. Phartnacol. Therap. 13, 148153. Administration of acetylsalicyclic acid (ASA) in the dog may cause gastric mucosal damage. Enteric-coated tablets protect the canine stomach during oral ASA medication. A therapeutic plasma salicylate concentration can be attained using enteric-coated ASA tablets at a dose rate of 25 mg/kg body wt, administered every 8 h. Six beagle dogs were given enteric-coated ASA tablets (500 mg) orally, in a 5-day cross-over experiment on two different feeding regimens: i.e. feeding once daily (Group I) or 8 hourly (Group 11). Results demonstrate that feeding regimen strongly influences the plasma salicylate concentration pattern. Subtherapeutic mean plasma salicylate concentrations were found in both groups. In Group I1 the standard deviation (SD) of the mean plasma salicylate concentration was larger than that of Group I. T h e minimal plasma salicylate concentration never reached detectable levels in Group 11. In both groups large numbers of tablets were vomited. Gastric evacuation o f the ASA tablets is comparable to indigestible solid particles; their removal was dependent on the interdigestive gastric motility. I t is concluded that large enteric-coated ASA tablets are not suitable for therapeutic use in small clogs.

R . C . Nap, Department of Clinical Sciences of Conipmion Animnls, Ulrrrhl University, P O Box 80.154, 3508 TD, Utrecht, the h'ellrerlmrrls

INTRODUCTION In the dog, aspirin or acetylsalicylic acid (ASA) is very irritant to the gastric mucosa, and may cause emesis, gastric haemorrhage and abdominal pain (Bonneau el al., 1972, Davison et al., 1966). T h e local effect after oral ASA administration is of major importance (Davison et al., 1966). Enteric (phthalate) coated tablets are therefore used in human and veterinary medicine to protect the gastric mucosa in oral medication. Gastric mucosal damage is significantly reduced by entericcoated ASA medication compared with both plain and buffered ASA (EcotrinB, 500 mg ASA, diameter 12 mm; Smith, Kline and French, Inc., Philadelphia, PA) (Lipowitz et 148

al., 1986). To achieve therapeutic plasma salicylate concentrations in the dog entericcoated ASA tablets are given at a dose rate of 25 mg/kg body wt 8 hourly (q8h) (Lipowitz et al., 1986). Disadvantages of the use of enteric-coated ASA tablets are the delay in reaching therapeutic plasma salicylate concentrations (50 mg/l), and the larger standard deviation of the mean (SD) when comparing enteric-coated ASA medication with both plain and buffered ASA (Leonards & Levy, 1965; Lipowitz et al., 1986). Both disadvantages may be due to a delay in gastric expulsion as well as to changes in intestinal motility (Lipowitz el al., 1986). To our knowledge there are no reports in the veterinary literature concerning gastric

Gastric retention of aspirin tablets in dogs

149

retention of enteric-coated tablets. In man, gastric retention of enteric-coated tablets appears to be related to pyloric diseases in most cases (Baum, 1984). Vomiting of large numbers of tablets, and thus insufficient analgesia during enteric-coated ASA therapy in canine patients, has been reported to us by veterinary practitioners (R. C. Nap, unpublished observations). Gastric motility and evacuation in the dog are markedly influenced by a variety of factors related to food intake including volume, caloric density, digestibility, viscosity, and particle dimensions (Hinder & Kelly, 1977; Kelly, 1981; Prove & Ehrlein, 1982; Burrows et al., 1985; Kruiningen et al., 1987; Hall et al., 1988). Gastric retention of ASA-containing enteric-coated tablets will result in a delay in absorption. However, no reports are available on the influence of the feeding regimen on the bioavailability of enteric-coated ASA. In the present study, large enteric-coated ASA tablets were admipistered to beagle dogs. T h e effect of different feeding regimens on the plasma salicylate concentration, which was taken as a parameter for gastric tablet retention, was studied.

08.00 h - the ward routine feeding schedule -whereas dogs in Group I1 received aliquots of 150 g each, three times daily, at 08.00 h, 16.00 h and 24.00 h. After 3 days of adaptation to the feeding regimen, dogs in both groups received the first ASA medication (one tablet per dog) 8 h after the 08.00-h food intake on Day 1. T h e phthalate-coated ASA tablets (Enterosarine@, 500 mg, diameter 13 mm; ICN Pharmaceuticals Holland bv Zoetermeer, the Netherlands) were administered q8h. T h e use of intact tablets resulted in doses ranging from 30.1 to 40.3 mg/kg body wt q8h. Tablet administration always preceded access to food. Dogs in both groups received a total number of 13 tablets throughout the experiment (Figs 1 and 2). Blood samples for plasma salicylate concentration were taken at 8 (= 16.00 h), 12, 16, 18, 20, 22 and 24 h, and then every 4 h for 104 h. During the experiment all excreta in the runs were screened for tablets. At 120 h, dogs in Group I1 returned to the single daily feeding schedule. T h e plasma salicylate concentration was measured using the colorimetric method according to Trinder (1954).

METHODS

RESULTS

Animals

In Group I (Fig. 1) the mean plasma salicylate concentration curve showed a 24-h interval pattern, the first maximum (133 mg/l) was measured at 24 h, i.e. 16 h after the initial drug administration. Mean plasma salicylate concentration exceeded 50 mg/l 12 h after initial drug administration. T h e plasma salicylate concentration curve in individual dogs also peaked at 24-h intervals. Although the minimal plasma salicylate concentration in individual dogs in Group I was frequently lower than 50 mg/l, the mean plasma salicylate concentration after 28 h exceeded 50 mg/l, except at 84 and 108 h when 47 rrig/l was recorded. T h e maximal plasma salicylate concentration measured in one dog was 267 mg/l at 68 h. In Group 11 (Fig. 2), the mean plasma salicylate concentration did not increase until 14 h after initial medication. T h e mean plasma salicylate concentration ranged between 41 and 117 mg/l. T h e maximal plasma

Six adult beagles (five males, one female) weighing 12.4-16.6 kg were used. Based upon physical examination, white-blood-cell count, and serum biochemistry profile, all dogs were considered to be in good health. T h e dogs were housed in individual runs, and fed daily with 450 g of commercial dry dog food (Doko, Trouw Nederland bv, Putten, the Netherlands). There. was free access to drinking water. Experimental procedure

In a cross-over design study the animals were randomly divided into two groups. Each dog in either group was fed 450 g of commercial dry dog food per day. Groups only differed with respect to the feeding regimen, i.e. dogs in Group 1 were fed once daily at

150 R. C. Nap et al.

250-

200-

c 0

-2 U

150-

100-

-0 a 50n-

. .

. . . . . . . . . .

120

Time ( h )

FIG. 1. Group 1. Mean plasma salicylate concentrations and ranges after administration of one enteric-coated aspirin tablet (500 mg) 8qh in six beagle dogs on a single daily feeding regimen: ( 0 )tablet administration; food administration 450 g ( 4 ).

250

0 -

150-

100-

0 In

50-

. .

Time ( h )

FIG. 2. Group 11. Mean plasma salicylate concentrations and ranges after administration of o n e entericcoated aspirin tablet (500 mg) 8qh in six beagle dogs on a three-times-daily feeding regimen: ( 0 ) tablet administration: food administration 150 g ( f ); and 450 g ( 4 ).

salicylate concentration measured was 233 mg/l in one dog at 100 h. T h e plasma salicylaie concentration of individual dogs in Group I1 varied markedly (Fig. 3), and throughout the experiment subdetectable concentrations were found. Vomiting of tablets occurred in both groups. I n Group I. one dog vomited two tablets, which were found at

128 h. In Group 11, one dog vomited two tablets after 24 h. A second dog, in which no detectable plasma salicylate concentration was measured throughout the experiment, vomited nine tablets between 144 a n d 152 h. In two dogs in Group 11, partly digested enteric-coated tablets were found in the faeces at 152 h.

Gastric retention of aspirin tablets in dogs

151

300-

250200150-

100-

500I

’

{

t i i i i i i i i i i i i i t 4

120

Time ( h )

FIG. 3. Group 11. Plasma salicylate concentrations in two beagles after administration of one enteric-coated aspirin tablet (500 mg) Sqh, on a three-times-daily feeding regimen: ( 0 ) tablet administration; food administration 150 g ( t ): and 450 g ( 4 ).

DISCUSSION The results of this study demonstrate major differences between both groups with regard to the initial plasma salicylate concentration rise, the mean, and the standard deviation of the mean plasma salicylate concentration (Figs I and 2). In Group I there was a marked correlation between the feeding regimen and the mean plasma salicylate concentration. In Group 11 the initial rise in the mean plasma salicylate concentration was delayed when compared to dogs of Group I and the mean plasma salicylate concentration pattern was unrelated to the feeding regimen. In dogs, plasma salicylate concentrations less than 50 mg/l are considered to be subtherapeutic (Yeary & Brant, 1975; Davis, 1980). Although the oral dose ranged from 30.1 to 40.3 mg/kg b o d y wt, mean plasma salicylate values below 50 mgA were observed in Group I at 84 and 108 h, and at 48 h in Group 11, whereas in individual dogs subtherapeutic plasma salicylate concentrations were frequently found in Group 11. T h e plasma salicylate concentrations in individual dogs were invariably less than 300 mgA, a level which is considered to be toxic (Davis, 1980). In this study the major differences in plasma salicylate concentration patterns be-

tween Groups I and I1 can be explained on the basis of gastric motility. T h e gastric emptying pattern in the dog has been reported to differ for liquids, partially digestible solids and solid particles (Hinder & Kelly, 1977; Kelly 1981). In addition, the size of indigestible solids is important; indigestible solid particles (7 mm) were not removed from the gastric lumen until 6-8 h after food intake (Code & Marlett, 1975; Hinder & Kelly, 1977; Banta ef al.. 1979; Kelly, 1981). During the post-prandial contraction phase the lumen of the pyloric opening is minimal and only liquids and very small particles are removed from the stomach. Six to eight hours after food intake, the pyloric opening dilates during phase three, ‘interdigestive’ or ‘fasting’ contractions and indigestible solid particles are removed from the canine stomach. Feeding postpones these so-called ‘gastric housekeeper’ contractions for 6-8 h (Code & Marlett, 1975; Hinder & Kelly, 1977; Kelly, 1981). Therefore, in this study the initial dosing was given 8 h after food intake, whereas in Group I1 the 8-h feeding interval was set. From the delay in the initial increase in plasma salicylate concentration, as well as the unpredictable concentration curve in individual dogs in Group 11, it is concluded that the 8-h feeding interval in fact did delay the pyloric passage of tablets. I n one dog in

152 R. C. Nap et al. Group I1 no detectable salicylate concentration was found throughout the experiment. After returning to a 24-h feeding interval at 120 h (08.00 h on Day 6), this dog vomited nine tablets. This is strongly indicative of a complete inhibition of interdigestive phasethree contractions in individual dogs by repeated food intake. The enteric-coated tablets used in the present study and those used by Lipowitz el al. (1986), had a diameter of 13 and 12 mm, respectively. The phthalate coating prevents gastric digestion of the tablets. It is therefore suggested that these tablets should be considered as indigestible solid particles when discussing gastric emptying. The minor differences in plasma ASA concentration caused by concurrent food intake during 3 h after drug administration, as reported by Richez et al. (1980) using nonenteric-coated ASA, are unlikely to have significantly influenced the results in this study. The present results indicate that gastric retention of the tablets occurs in healthy beagle dogs, whereas in man retention is related to pyloric diseases (Baum, 1984); to our knowledge this phenomenon does not occur in healthy subjects. Vomiting several tablets at the same time in Group I indicates that gastric retention of tablets does occur in dogs on a single daily feeding regimen. A prolonged interval between feeding and initiation of phasethree interdigestive contractions cannot be excluded (Itoh el al., 1977). Partially digested tablets were found in the faeces of dogs in Group I1 after the dogs were changed to a once-daily feeding pattern. Tablet transport by migrating motility complexes (Weisbrodt, 1981). originating from the stomach and descending along the intestinal tract, might have caused a transit time insufficient for complete disintegration of tablets. Our results demonstrate that stable therapeutic plasma salicylate concentrations are not to be expected in dogs on an oral entericcoated aspirin medication at a dose rate of 25 mglkg b o d y wt q8h, using the large tablets. This is in accordance with the results obtained by Lipowitz et al. (1986). From the present study it is concluded that the large phthalatecoated ASA tablets are not suitable for thera-

peutic use in small dogs. Moreover, it is tempting to suggest that gastric tablet retention will occur in any oral medication in small dogs when a similar type of enteric-coated tablets is used.

ACKNOWLEDGMENTS Thanks are due to Drs H. A. W. Hazelvinkel and P. Stolk for their help in preparing the manuscript. REFERENCES Banta, C.A., Clemens. E.T., Krinsky, M.M. & Sheffy, B.E. (1979) Sites of organic acid production and patterns of digestal movements in the gastrointestinal tract of dogs. Journal of Nutrition, 109, 1592-1600. Baum, J. (1984) Enteric-coated aspirin and the problem of gastric retention. Journal of Rheumatology, 11, 250-25 1. Bonneau, N.H., Reed, J.H., Pennock, P.W. & Little. P.B. (1972) Comparison of gastrophotography and contrast radiography for diagnosis of aspirin induced gastritis in the dog. J o u m l of the Amen'can Veterinnly Medical Associafivn, 161, 190-198. Burrows, C.F., Bright, R.M. & Spencer, C.P. (1985) Influence of dietary composition on gastric emptying and motility in dogs: potential involvement in acute gastric dilatation. American Journal 7f Veterinary Research, 46, 2609-26 12. Code, C.F. & Marlett, J.A. (1975) T h e interdigestive myo-electric complex of the stomach and small bowel of dogs. J o u m l of Physiulugy. 246, 289-309. Davis. L.E. (1980) Clinical pharmacology of salicylates. J o u m l of the American Veterinary Medical Association, 176, 65-66. Davison, C., Hertig, D.H. & DeVine, R. (1966) Gastric hemorrhage induced by nonnarcotic analgetic agents in dogs. Clinical Phanacolog TheraB, 7, 239-249. Hall, J.A., Burrows, C.F. & Twedt, D.C. (1988) Gastric motility in dogs, Part I. Normal gastric function. Compendium of Continuing Education for the Practicing Veterinarian, 10, 1282-1293. Hinder, R.A. & Kelly, K.A. (1977) Canine gastric emptying of solids and liquids. American Journal of Physiology, 233, E3354340. Itoh, Z., Aizawa, I., Takeuchi, S. & Takayanagi, R. (1977) Diurnal changes in gastric motor activity in conscious dogs. American Journal of Digestive Diseases, 22, 117-124. Kelly, K.A. (1981) Motility of the stomach and gastroduodenal junction. In Physiology of the Gastrointrstinal Tract. Ed. Johnson, L.R. pp. 197241. Raven Press, New York. Kruiningen, H.J. van, Wojan, L.D., Stake, P.E. &

Gastric retention of aspirin table& in dogs Lord, P.F. (1987) The influence of diet and feeding frequency on gastric function in the dog. Journal of liu Atnerican Animal Hospilal Association, 23, 145-153. Leonards, J.R. & Levy, G. (1965) Absorption and metabolism of aspirin administered in entericcoated tablets. Journal of the American Medical Association, 193, 93-98. Lipowitz, A.J., Boulay, J.P. & Klausner, J.S. (1986) Serum salicylate concentrations and endoscopic evaluation of the gastric mucosa in dogs after oral administration of aspirin containing products. American Journal of Veterinary Research, 47, 15861589. Prove, J. & Ehrlein, H.J. (1982) Motor function of gastric antrum and pylorus for evacuation of low

153

and high viscosity meals in dogs. Gut, 23, 150156. Richez, P., Regnier, A. & Ruckebush, Y. (1980) Influence of food intake on the absorption of lysine-acetylsalicylatein dogs. Journal of Veterinury Pharmacology and Therapeuliu, 3, 121-124. Trinder, P. (1954) Rapid determination of salicylate in biological fluids. The Biochemical Journal, 57, 301-303. Weisbrodt, N.W. (1981) Motility of the small intestine. In Physiology of the Gastrointestinal Tract. Ed. Johnson, L.R. pp. 411443. Raven Press, New

York. Yeary, R.A. & Brant, R.J. (1975) Aspirin dosages for the dog. Journal of the American Veterinary Medical Association, 167, 63-64.