The site of inversion of R(-)-ibuprofen: studies using rat in-situ isolated perfused intestine/liver preparations
| Autor: | Crewe Hk, Tucker Gt, Jeffrey P, Wright Pa, Bye A |
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| Rok vydání: | 1991 |
| Předmět: |
Male
medicine.medical_specialty Pharmaceutical Science Lumen (anatomy) Ileum Ibuprofen Biology Gastroenterology Jejunum Internal medicine medicine Animals Intestinal Mucosa Pharmacology organic chemicals Rats Inbred Strains Stereoisomerism Metabolism Molecular biology Small intestine Rats Perfusion medicine.anatomical_structure Liver Duodenum Enantiomer |
| Zdroj: | The Journal of pharmacy and pharmacology. 43(10) |
| ISSN: | 0022-3573 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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