Planta Med 2002; 68(8): 714-718
DOI: 10.1055/s-2002-33792
Original Paper
Pharmacology
© Georg Thieme Verlag Stuttgart · New York

Evaluation of Salicin as an Antipyretic Prodrug that does not Cause Gastric Injury

Teruaki Akao1 , Tetsuro Yoshino1 , Kyoich Kobashi1 , Masao Hattori2
  • 1Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan
  • 2Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan
Further Information

Publication History

Received: October 31, 2001

Accepted: February 3, 2002

Publication Date:
09 September 2002 (online)

Abstract

Pharmacokinetic and pharmacological studies were performed to compare the antipyretic effects of salicin (SL), saligenin (SG, an aglycone of SL) and salicylic acid (SA, an active metabolite of SL) in rats. When SL was administered orally to rats, SA appeared slowly in the plasma and levels increased gradually, in contrast to the rapid appearance observed after oral administration of sodium salicylate (SANa) or SG. Orally administered SL did not affect the rectal temperatures of afebrile rats at a dose of 5 mmol/kg; at this dose, SANa and SG lowered body temperature significantly. However, it significantly reduced yeast-induced fever, producing a normal body temperature, and completely prevented fever when administered simultaneously with yeast. SL did not induce gastric lesions even at a dose of 5 mmol/kg; conversely, SANa and SG induced severe gastric lesions in a dose-dependent manner at 1, 2.5 and 5 mmol/kg. Poor absorption of SL and rapid absorption of SA and SG were confirmed in an in vivo system, as well as in an in vitro system using everted rat jejunal sacs. Only small amounts of SA and SG were detected in the intestinal tracts of rats 1 h after oral administration, whereas more than 50 % of an SL dose was recovered as SL and SG from the intestinal tracts 1 h after treatment and 15.8 % of the dose was still present as SG 4 h after administration. When given to germ-free rats, 19.8 % of the SL dose was recovered intact, mainly from the cecum, and no SG was detected even at 4 h after treatment. These results indicate that SL is a prodrug which is gradually transported to the lower part of the intestine, hydrolyzed to SG by intestinal bacteria, and converted to SA after absorption. It thus produces an antipyretic action without causing gastric injury.

Abbreviations

SL:salicin

SG:saligenin

SA:salicylic acid

SANa:sodium salicylate

NSAIDs:non-steroidal anti-inflammatory drugs

References

  • 1 Lanza F L, Royer GL J r, Nelson R S, Chen T T, Seckman C E, Rack M K. The effect of ibuprofen, indomethacin, aspirin, naproxen, and placebo on the gastric mucosa of normal volunteers.  Digestive Diseases and Sciences. 1979;  24 823-8
  • 2 Weissmann G. Aspirin. Scientific American. 1991: 58-64
  • 3 Satinoff E. Salicylate: Action of normal body temperature in rats.  Science. 1972;  176 532-3
  • 4 Scales W E, Kluger M J. Effect of antipyretic drugs on circadian rhythm in body temperature of rats.  American Journal of Physiology. 1987;  253 R306-313
  • 5 Festenstein G N. Substrates for rumen β-glucosidase.  Biochemical Journal. 1958;  70 49-51
  • 6 MacLagan T J. The treatment of acute rheumatism by salicin.  Lancet. 1876;  1 342-3
  • 7 Tormey H J, Wood J D. Chemotheraphy of rheumatic fever and subacute bacterial endocarditis. Science Studies, St.  Bonaventure Collection. 1944;  12 (No.2) 3-12
  • 8 European Scientific Cooperative on Phytotherapy Monographs (ESCOP). Salicis Cortex Fascicule 4 ISBN 1-90 164-00-0. The Netherlands; 1997
  • 9 Steinegger E, Hovel H. Analytische und biologische Untersuchungen an Salicaceen-Wirkstoffen, insbesondere an Salicin.  Pharmaceutica Acta Helvetiae. 1972;  47 222-34
  • 10 Fotsch G, Pfeifer S, Bartoszek M, Frank P, Hiller K. Biotransformation der Phenolglycoside Leiocarposid und Salicin.  Pharmazie. 1989;  44 555-8
  • 11 Fotsch G, Pfeifer S. Die Biotransformation der Phenolglycoside Leicarposid und Salicin-Beispiele für Besonderheiten von Absorption und Metabolismus glycosidischer Verbindungen.  Pharmazie. 1989;  44 710-2
  • 12 Fotsch G, Pfeifer S. Vergleichende Serumspiegeluntersuchung von Salicylsäure nach oraler Applikation von Salicin bzw. Natriumsalicylat in Ratten.  Pharmazie. 1990;  45 535-6
  • 13 Cham B E, Johns D, Bochner F, Imhoff D M, Rowland M. Simultaneous liquid-chromatographic quantitation of salicylic acid, salicyluric acid, and gentisic acid in plasma.  Clinical Chemistry. 1979;  25 1420-5
  • 14 Barr W H, Riegelman S. Intestinal drug absorption and metabolism I: Comparison of methods and models to study physiological factors of in vitro and in vivo intestinal absorption.  Journal of Pharmaceutical Sciences. 1970;  59 154-63
  • 15 Mallett A K, Bearne C A, Rowland I R, Farthing M JG, Cole C B, Fuller R. The use of rats associated with a human faecal flora as a model for studing the effects of diet on the human gut.  Journal of Applied Bacteriology. 1987;  63 39-45
  • 16 Kakemi M, Kobayashi T, Mamuro C, Ueda M, Koizumi T. Pharmacokinetic analysis of pharmacological effects and drug disposition. II. Effects of salicylamide on afebrile rats.  Chemical and Pharmaceutical Bulletin. 1976;  24 2254-7
  • 17 Kakemi M, Masuda K, Ueda M, Koizumi T. Pharmacokinetic analysis of pharmacological effects and drug disposition. Acetaminophen and 4-aminoantipyrine.  Chemical and Pharmaceutical Bulletin. 1975;  23 736-45
  • 18 Chrubasik S, Eisenberg E, Balan E, Weinberger T, Luzzati R, Conradt C. Treatment of low back pain exacerbations with willow bark extract: A randomized double-blind study.  American Journal of Medicine. 2000;  109 9-14
  • 19 Schmid B, Ludtke R, Selbmann H K, Kotter I, Tschirdewahn B, Schaffner W, Heide L. Effectiveness and tolerance of standardized willow bark extract in arthrosis patients. Randomized, placebo controlled double-blind study.  Zeitschrift fur Rheumatologie. 2000;  59 314-20

Dr. T. Akao

Faculty of Pharmaceutical Sciences

Toyama Medical and Pharmaceutical University


2630 Sugitani

Toyama 930-0194

Japan

Email: ta0113@ms.toyama-mpu.ac.jp

Fax: +81(076)434-4656