title: Hepatic and renal toxicities of indomethacin acid, salt form and complexed forms with hydroxypropyl-β-cyclodextrin on Wistar rats after oral administration.
abstract: Indomethacin (IM), a non-steroidal anti-inflammatory drug, has the capacity to induce hepatic and renal injuries when administrated systemically. The aim of this study is to assess the IM absorption from complexed forms when orally administered to rats, by means of a comparative evaluation of its capacity to induce hepatic and renal injury in different forms, namely IM acid, IM sodium salt or IM complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD), using freeze- and spray-drying methods. A total of 135 Wistar rats weighing 224.4 ± 62.5 g were put into 10 groups. They were allowed free access to water but were maintained on fast for 18 h before the first administration until the end of the experiment. Water and HP-β-CD (control groups) and IM acid form, IM trihydrated-sodium-salt and IM-HP-β-CD spray- and freeze-dried, at normal and toxic doses (test groups), were orally administered once/day for 3 days. Seventy-two hours after the first administration, the animals were sacrificed and a fragment of the liver and one kidney were collected and prepared for histopathological evaluation. Lesion indexes (rated 0/4 for liver and 0/3 for kidney) were developed and the type of injury scored according to the severity of damage. A statistical analysis of the severity and incidence of lesions was carried out. Animals administered with IM complexed forms showed similar hepatic and renal lesions, both in toxic and therapeutic doses, when compared with those observed in animals administered with IM acid or salt forms. This suggests that under the present experimental conditions, IM is equally absorbed from the gastrointestinal tract, independently of the administered IM form.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Ribeiro-Rama
authors.forename: Isabel Vitória
authors.initials: IV
authors.lastname: Figueiredo
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: Veiga
authors.forename: Maria Margarida
authors.initials: MM
authors.lastname: Castel-Branco
authors.forename: António M Silvério
authors.initials: AM
authors.lastname: Cabrita
authors.forename: Maria Margarida
authors.initials: MM
authors.lastname: Caramona
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D005079:Excipients / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D005612:Freeze Drying; D041981:Gastrointestinal Tract / Q000502:physiology; D007213:Indomethacin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D023421:Models, Animal; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013272:Stomach Diseases / Q000517:prevention & control; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D005079:Excipients; D047392:beta-Cyclodextrins; C033053:beta-cyclodextrin, indomethacin drug combination; D007213:Indomethacin