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The Site of Inversion of R(-)-ibuprofen: Studies Using Rat In-Situ Isolated Perfused intestine/liver Preparations

The Site of Inversion of R(-)-ibuprofen: Studies Using Rat In-Situ Isolated Perfused intestine/liver Preparations

P Jeffrey, G T Tucker, A Bye, H K Crewe, P A Wright

J Pharm Pharmacol. 1991 Oct;43(10):715-20.

PMID: 1682447

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., micrograms 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 S(+)-ibuprofen to the jejunum (n = 5) resulted in AUC values of 1864 +/- 238 for S(+)-ibuprofen and 6 +/- 3 for R(-)-ibuprofen. After addition of R(-)-ibuprofen (30 micrograms 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 S(+)-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP3585522	Ibuprofen Impurity N		3585-52-2	Price

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