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Órgano Oficial de la Asociación Mexicana de Hepatología

2009, Number 2

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Ann Hepatol 2009; 8 (2)

Pharmacokinetics of acemetacin and its active metabolite indomethacin in rats during acute hepatic damage and liver regeneration

Chávez-Piña AE, Favari L, Castañeda-Hernández G

Language: English
References: 25
Page: 141-147
PDF size: 132.25 Kb.


Text Extraction

Background and aim: The pharmacokinetics of acemetacin, a non-steroidal anti-inflammatory drug which is biotransformed to indomethacin by hepatic first-pass effect, was examined during the necrotic and regeneration phases resulting from acute hepatitis induced by carbon tetrachloride (CCl4). Material and methods: Acute hepatitis was induced by oral CCl4 administration to male Wistar rats. On days 0, 1 and 3 after the insult, liver histological analysis was performed, biochemical markers of liver damage and regeneration were measured, and the pharmacokinetics of oral acemetacin and of its active metabolite, indomethacin, were determined. Results: One day after CCl4 administration, liver necrosis was apparent and there was an increase in the circulating levels of indicators of liver damage and regeneration with regard to control conditions. Acemetacin bioavailability was increased, although not in a statistically significant manner. On the other hand, indomethacin bioavailability was significantly reduced. By day 3, histological analysis revealed liver recovery, although not complete, while biochemical indicators of hepatic damage had reverted either totally or partially. Markers of liver regeneration were still increased. Bioavailability acemetacin and indomethacin was comparable to control values. In conclusion: Indomethacin bioavailability after oral administration of its precursor, acemetacin, is significantly reduced by acute hepatitis produced by CCl4. Pharmacokinetic alterations, as liver damage, are reversible, but do not require complete liver regeneration to return to basal conditions.


REFERENCES

  1. Boltze K, Brendler O, Jacobi H, Optiz W, Raddatz S, Seidel PR, Volbrecht D. Chemical structure and anti-inflammatory activity in the group of substituted indole-3 acetic acids. Arzneimittelforschung 1980; 30: 1314–25.

  2. Jacobi H, Dell HD. On the pharmacodynamics of acemetacin. Arzneimittelforschung 1980; 30: 1348–62.

  3. Bori-Segura G, Torres A, Herrera LE, Olguín J. Efficacy and tolerability of acemetacin, a non-steroidal anti-inflammatory drug, in Mexican patients: result of the ETAPAM study. Proc West Pharmacol Soc 2002; 45: 104–7.

  4. Chou CT, Tsai YY. A double-blind, randomized, controlled parallel group study evaluating the efficacy and safety of acemetacin for the management of osteoarthritis. Int J Clin Pharmacol Res 2002; 22: 1–6.

  5. Jones RW, Collins AJ, Notarianni LJ, Sedman E. The comparative pharmacokinetic of acemetacin in young subjects and elderly patients. Br J Clin Pharmacol 1991; 31: 543–45.

  6. Dell HD, Doersing M, Jacobi H, Kamp R. Biochemical studies on Acemetacin experimental test in animals. Arzneimittelforschung 1980; 30(II): 1371-83.

  7. Surborg H. Comparative metabolic studies on 14C-labelled acemetacin and indomethacin in rats. Arzneimittelforschung 1980; 30(II): 1384-91.

  8. Dell HD, Doersing M, Fischer W, Jacobi H, Kamp R, Köhler G, Schöllnhammer G. Metabolism and pharmacokinetics of acemetacin in man. Arzneimittelforschung 1980; 30(II): 1391-98.

  9. Li DM, Lu WL, Wang XQ, Wang JC, Zhang H, Zhan RJ, Wang GL, et al. Pharmacokinetics of indomethacin, a metabolite of acemetacin, following a single dose and multiple doses administered as acemetacin sustained-release tablets in healthy male volunteers. Journal of Health Science 2005; 51(3): 308-16.

  10. Chávez-Piña AE, McKnight W, Dicay M, Castañeda-Hernández G, Wallace JL. Mechanism underlying the anti-inflammatory activity and gastric safety of acemetacin. Br J Pharmacol 2007; 152(6): 930-38.

  11. Chávez-Piña AE, Vong L, McKnight W, Dicay M, Zanardo RC, Ortiz MI, Castañeda-Hernández G, Wallace JL. Lack of effects of acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety. Br J Pharmacol 2008; 155(6):857-64.

  12. Boobis AR, Brodie MJ, Kahn GC, Fletcher DR, Saunders JH, Davies DS. Monooxygenase activity of human liver in microsomal fractions of needle biopsy specimens. Br J Clin Phamacol 1980; 9(1):11-19.

  13. Favari L, Castañeda-Hernández G, Hoyo-Vadillo C. Pharmacokinetics and pharmacodynamics of naproxen in acute experimental hepatitis. Arzneimittelforschung 1993; 43(6): 675-9.

  14. Rivera-Espinosa L, Muriel P, Ordaz-Gallo M, Perez-Urizar J, Palma-Aguirre A, Castaneda-Hernandez G. Ketorolac pharmacokinetics in experimental cirrhosis by bile duct ligation in the rat. Ann Hepatol 2003; 2: 175–81.

  15. Reyes-Gordillo K, Muriel P, Castañeda-Hernández G, Favari L. Pharmacokinetic of diclofenac in rats intoxicated with CCl4 and in the regenerating liver. Biopharm Drug Dispos 2007; 28:415-22.

  16. Doshi J, Luisada-Opper A, Leevy CM. Microsomal pentobarbital hydroxylase activity in acute viral hepatitis. Proc Soc Exp Biol Med 1972; 140(2): 492-95.

  17. Gibaldi M, Boyes RN, Feldman S. Influence of first-pass effect on availability of drugs on oral administration. J Pharm Sci 1971; 60(9):1338-40.

  18. Norma Oficial Mexicana NOM-062-ZOO-1999. http://www.fmvz.unam.mx/fmvz/principal/archivos/062ZOO.PDF

  19. Glossman M, Neville DM. Glutamyl transferase in kidney brush border membranas. FEBS Lett 1972; 19: 340-44.

  20. Reitman S, Frankel S. A colorimetric method for determination of serum oxaloacetic and glutamic pyruvic transaminases. Am J Clin Pathol 1957; 28: 56-63.

  21. Mourelle M, Villalón C, Amezcua JL. Protective effect of colchicine on acute liver damage induced by carbon tetrachloride. J Hepatol 1988; 6: 337-342.

  22. Muriel P. Nitric oxide protection of rat liver from lipid peroxidation, collagen accumulation, and liver damage induced by carbon tetrachloride. Biochem Pharmacol 1998; 56: 773-79.

  23. Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol 2003; 33: 105-36.

  24. Cruz L, Castañeda-Hernández G, Navarrete A. Ingestion of chilli pepper (Capsicum annuum) reduces salicylate bioavailability after oral asprin administration in the rat. Can J Physiol Pharmacol 1999; 77: 441-6.

  25. Nakajima M, Inoue T, Kuroiwa Y. Cytochrome P450 2C9 catalyzes Indomethacin ï-demethylacion in human liver microsomas. Drug Metabolism and Disposition. 1997; 26(3): 261-67.




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