The Site of Inversion of R(–)-Ibuprofen: Studies Using Rat In-situ Isolated Perfused Intestine/liver Preparations

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Abstract
The site of metabolic inversion of R(–)-ibuprofen to the pharmacologically active S(+)-enantiomer has been investigated using an array of in-situ rat perfused organ preparations allowing vascular perfusion (55–60 min) of the separate or combined intestine and liver. After addition of R(–)-ibuprofen (20 mg kg−1 body weight) to the closed (static) lumen of isolated 25 cm lengths of duodenum, jejunum or ileum, and single-pass vascular perfusion, both isomers were measured in the lumen and in vascular perfusate plasma (mean plasma AUC values (±s.d., μg mL−1 min, n = 5) R(–)-ibuprofen: 1669±115 (duodenum), 1687 ± 203 (jejunum), 2061 ±188 (ileum); S(+)-ibuprofen: 23 ± 6 (duodenum), 14 ±5 (jejunum), 26±1 (ileum)). Addition of the same dose of 5(+)-ibuprofen to the jejunum (n = 5) resulted in AUC values of 1864 ± 238 for 5(+)-ibuprofen and 6±3 for R(–)-ibuprofen. After addition of R(–)-ibuprofen (30 μg mL−1) to the recirculating vascular perfusate (100 mL) of the entire small intestine (n = 6) AUC values were 1647 ± 34 for R(–)-ibuprofen and 13 ± 3 for S(+)-ibuprofen. The same dose of R(–)-ibuprofen to combined intestine/liver (n = 6) and liver only preparations (n = 6) gave AUC values of 1011 ± 25 and 1021 ± 49 for R(–)-ibuprofen and 220 ± 28 and 238 ± 22 for 5(+)-ibuprofen, respectively. In all experiments, except those involving perfusion of the combined intestine/liver and the liver, the concentrations of the isomer opposite to that administered could be accounted for solely by the level of enantiomeric impurity (1·3% for R(–)-ibuprofen and 0·6% for S(+)-ibuprofen). We conclude that inversion of R(–)-ibuprofen to the S(+) antipode occurs in the liver but does not occur on either mucosal or serosal sides of the small intestine of the rat.