Stereoselective Disposition of Sustained Release Microspheres of Ibuprofen Enantiomers in Rats: II. Acute Gastrointestinal Toxicity

Abstract

The purpose of this study was to examine acute gastrointestinal tract (GIT) toxicity caused by the pure enantiomers of ibuprofen in male Wistar rats. A 2 2 2 factorial design in which rats were randomly divided into eight experimental groups and a control group was used. They were dosed with the sustained release microsphere and conventional suspensions of ibuprofen enantiomers at 20 mg/kg and 40 mg/kg dose levels. Bethanechol chloride (5 mg/kg), a cholinomimetic agent, was administered 30 min after dosing to induce gastric irritation. Animals were euthanized at different time intervals up to 48 hr postdosing followed by excision of stomach and intestinal tract. Blood samples also were collected during this study by cardiac puncture and stereospecifically analyzed. Tissues were examined for lesions and hemorrhages macroscopically (75 magnification) using top and bottom illumination. Macroscopic evaluation of the tissue samples revealed significant differences in the GIT toxicity caused by S- and R-ibuprofen at the 40 mg/kg level (p < . 05), with S-ibuprofen being the more toxic form. Toxicity seen in the R-ibuprofen formulation may be both inherent and due to subsequent inversion to S-enantiomer. Toxicity was reduced significantly with the higher dose (40 mg/kg) of the encapsulated drug compared with the unencapsulated drug. At the 20 mg/kg dose level, no significant differences were observed between the two enantiomers. At this dose, encapsulation reduced toxicity but not significantly compared with unencapsulated ibuprofen. GIT toxicity was site-specific; high toxicity was seen in the stomach, very little toxicity was seen in the duodenum and jejunum, whereas relatively higher toxicity was observed in the ileum. High toxicity also was seen in the cecum and colon, evidenced by cecal ulcers. Monitoring plasma concentrations revealed that enough drug was released enough to subject GI mucosa to irritation. In all cases, the plasma concentrations and the AUC were higher for S- compared with R-ibuprofen. However, there was no correlation between the plasma levels and the toxicity seen in the GIT. A previous 7-hr study, carried out in our lab to assess GIT toxicity of racemic ibuprofen, showed that the racemate was more ulcerogenic at equivalent doses and within the same time interval. Encapsulation of ibuprofen significantly reduced GIT toxicity especially at the higher doses. S-ibuprofen caused greater toxicity compared with R-ibuprofen and GIT toxicity was site-specific. Greater toxicity caused by racemic ibuprofen has significant clinical implications.