title: Pharmacokinetics of acemetacin and its active metabolite indomethacin in rats during acute hepatic damage and liver regeneration.
abstract: OBJECTIVE
  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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sección Externa de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México, D.F., Mexico.
authors.forename: Aracely E
authors.initials: AE
authors.lastname: Chávez-Piña
authors.forename: Liliana
authors.initials: L
authors.lastname: Favari
authors.forename: Gilberto
authors.initials: G
authors.lastname: Castañeda-Hernández
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006498:Hepatectomy; D007213:Indomethacin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008115:Liver Regeneration; D008297:Male; D009336:Necrosis; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C026784:acemetacin; D002251:Carbon Tetrachloride; D007213:Indomethacin