ABSTRACT
To characterize the influence of nitric oxide (NO) donors on the intestinal absorption of macromolecules, the relationship between the release rate of NO from NO donors and their absorption-enhancing effects and the effects of several scavengers and generators on the absorption-enhancing effects of NO donor were investigated. The t1/2 values of the NO release rate from 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-1-propanamine (NOC5), 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-N-methyl-1-propanamine (NOC7) and N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine (NOC12) are 25, 5 and 100min, respectively. The absorption-enhancing effects of NO donors on the absorption of fluorescein isothiocyanate dextrans with an average molecular weight of 4400 (FD-4) are NOC5 > NOC7 > NOC12 in the colon. The lowest enhancing effect of NOC12 may be due to the slow rate of NO release. The enhancing effect of NOC7 rapidly disappeared compared with the effect of NOC5. The results raise the possibility that the difference between NOC5 and NOC7 on enhancing effect is related to the t1/2 of the NO release. The NOC7-induced enhancing effect was prevented by the co-administration of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide sodium salt (C-PTIO), an NO scavenger; tiron, an O2(-) scavenger; mannitol, an OH* scavenger, and deferoxamine, peroxynitrate scavenger. Pyrogallol, an O2(-) generator, potentiated the NOC7-induced enhancing effect. These results support a role for peroxynitrate, and possibly OH*, in the NO donor-induced intestinal enhancing effect.
Subject(s)
Fluorescein-5-isothiocyanate/analogs & derivatives , Intestinal Absorption/drug effects , Macromolecular Substances/metabolism , Nitric Oxide Donors/metabolism , 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/metabolism , 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology , Adenosine Triphosphate/metabolism , Animals , Benzoates/administration & dosage , Benzoates/metabolism , Benzoates/pharmacokinetics , Colon/drug effects , Colon/metabolism , Colon/pathology , Dextrans/chemistry , Dextrans/metabolism , Dextrans/pharmacology , Drug Synergism , Fluorescein-5-isothiocyanate/chemistry , Fluorescein-5-isothiocyanate/metabolism , Fluorescein-5-isothiocyanate/pharmacology , Free Radical Scavengers/metabolism , Free Radical Scavengers/pharmacology , Hydrazines/antagonists & inhibitors , Hydrazines/metabolism , Hydrazines/pharmacology , Hydroxyl Radical/metabolism , Imidazoles/administration & dosage , Imidazoles/metabolism , Imidazoles/pharmacokinetics , Intestinal Absorption/physiology , Macromolecular Substances/administration & dosage , Macromolecular Substances/pharmacokinetics , Male , Nitrates/metabolism , Nitric Oxide/metabolism , Nitric Oxide/pharmacology , Nitric Oxide Donors/classification , Nitric Oxide Donors/pharmacology , Nitroso Compounds/metabolism , Nitroso Compounds/pharmacology , Rats , Rats, Wistar , Superoxides/metabolism , Triazenes/metabolism , Triazenes/pharmacologyABSTRACT
Four fatty acid diesters (diethyl succinate, diethyl adipate, diethyl sebacate, and diisopropyl adipate) were used to study their enhancement effect on the permeation of four non-steroidal anti-inflammatory drugs (NSAIDs: ketoprofen, indomethacin, diclofenac sodium, and ibuprofen) through rat abdominal skin. With the diester pretreatment, drug permeation increased and the lag times decreased. No relationship was observed between the solubilities of the drugs in the diesters and the diester enhancement effects. The enhancement effect decreased with an increase of the drug lipophilicity, but increased with an increase of the lipophilic index of the diester up to about 3.5, after which the enhancement effect decreased or remained constant. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) was employed to investigate the biophysical changes in the stratum corneum lipids caused by the diesters. The FTIR results showed that treatment of the skin with diesters did not produce a blue shift in the asymmetric and symmetric C-H stretching peak positions. However, all of the above diesters showed a decrease in peak heights and areas for both asymmetric and symmetric C-H stretching absorbances in comparison with water treatment. These results suggested that the diesters were more effective for enhancing the penetration of hydrophilic drugs than lipophilic drugs, and the enhancing effect of lipophilic diesters was more effective than that of hydrophilic diesters. The enhancement effects of diesters may be due to their causing lipid extraction in the skin.
