title: Excellent absorption enhancing characteristics of NO donors for improving the intestinal absorption of poorly absorbable compound compared with conventional absorption enhancers.
abstract: The characteristics of NO donors, NOC5 [3-(2-hydroxy-1-(1-methylethyl-2-nitrosohydrazino)-1-propanamine), NOC12 [N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine] and SNAP [S-nitroso-N-acetyl-DL-penicillamine] as absorption enhancers for poorly absorbable drugs were examined in rats using an in situ closed loop method. They were compared with a group of conventional absorption enhancers including sodium glycocholate (NaGC), sodium caprate (NaCap), sodium salicylate (NaSal) and n-dodecyl-beta-D-maltopyranoside (LM). 5(6)-carboxyfluorescein (CF) was used as a model drug to investigate effectiveness, site-dependency, and concentration-dependency of the tested enhancers. Overall, the NO donors can improve the intestinal absorption of CF at low concentration (5 mM), whereas higher concentration was required for the conventional absorption enhancers to elicit the absorption enhancing effect. In the small intestine, SNAP was the most effective absorption enhancers, although its concentration (5 mM) was lower than the conventional absorption enhancers (20 mM). On the other hand, LM and NaCap as well as the three NO donors were effective to improve the colonic absorption of CF. In the regional difference in the absorption enhancing effects, the NO donors showed significant effects in all intestinal regions, whereas we observed a regional difference in the absorption enhancing effect of the other conventional absorption enhancers. In the conventional enhancers, the absorption enhancing effects were generally greater in the large intestine than those in the small intestine. LM and NaCap were ineffective in the jejunum, although they were effective for improving the absorption of CF in the colon. NaSal was ineffective in both the jejunum and the colon. The absorption enhancement produced by NO donors was greatly affected by increasing the enhancer concentration from 3 to 5 mM, but only a slight increase was obtained when the concentration was raised to 10 mM. Similar results were obtained for the other enhancers over the range of 10 to 20 mM, but the absorption enhancing effects of these enhancers were almost saturated above these concentrations. These results suggest that NO donors possess excellent effectiveness as absorption enhancers for poorly absorbable drugs compared with the conventional enhancers. They can enhance intestinal absorption of CF from all intestinal regions and they are effective at very low concentrations.
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan.
authors.forename: Gihan
authors.initials: G
authors.lastname: Fetih
authors.forename: Fawsia
authors.initials: F
authors.lastname: Habib
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.forename: Naoki
authors.initials: N
authors.lastname: Okada
authors.forename: Takuya
authors.initials: T
authors.lastname: Fujita
authors.forename: Mohammed
authors.initials: M
authors.lastname: Attia
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003652:Decanoic Acids / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000378:metabolism / Q000493:pharmacokinetics*; D005456:Fluorescent Dyes / Q000378:metabolism / Q000493:pharmacokinetics; D006000:Glycocholic Acid / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008320:Maltose / Q000031:analogs & derivatives / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012980:Sodium Salicylate / Q000494:pharmacology
chemical_list: C513644:3-(2-hydroxy-1-(1-methylethyl-2-nitrosohydrazino)-1-propanamine); D000277:Adjuvants, Pharmaceutic; D003652:Decanoic Acids; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006834:Hydrazines; C118603:NOC 12; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C110881:S-nitro-N-acetylpenicillamine; C411362:dodecyl maltopyranoside; C024098:6-carboxyfluorescein; C031071:decanoic acid; D008320:Maltose; D006000:Glycocholic Acid; D010396:Penicillamine; D012980:Sodium Salicylate