Differential effects of anionic, cationic, nonionic, and physiologic surfactants on the dissociation, alpha-chymotryptic degradation, and enteral absorption of insulin hexamers.
Various surfactants were investigated to compare their effects on insulin dissociation, alpha-chymotryptic degradation, and rat enteral absorption. With a circular dichroism technique, sodium dodecyl sulfate (SDS) at a 5 mM concentration was found to completely dissociate porcine-zinc insulin hexamers (0.5 mg/ml) into monomers. The catalytic activity of alpha-chymotrypsin (0.5 microM) was also abolished by 5 mM SDS. When insulin was injected into the distal jejunum/proximal ileum segment of the rat, 5 mM SDS greatly enhanced its pharmacological availability, from a negligible value to 2.8%. Being a cationic surfactant, hexadecyl trimethylammonium bromide (CTAB) also efficiently dissociated insulin hexamers at concentrations of 1-5 mM. However, extensive charge-charge interaction was observed below a CTAB concentration of 0.6 mM, leading to insulin precipitation at a molar CTAB:insulin ratio of 1:1 to 2:1. An alpha-chymotryptic degradation study also revealed near-complete dissociation of insulin hexamers at 1 mM CTAB. Above 1 mM, however, CTAB acted as an enzyme inhibitor, most likely by means of charge repulsion. Enteral absorption studies showed a much lower pharmacological availability, only 0.29%. Nonionic surfactants such as Tween 80 and polyoxyethylene 9 lauryl ether were ineffective in dissociating insulin hexamers. Tween 80, at 5 mM, neither significantly altered the alpha-chymotryptic degradation pattern nor enhanced the enteral absorption of insulin. The relative effectiveness of different species of bile salts on insulin hexamer dissociation appeared to be similar. Sodium glycocholate at a 30 mM concentration also significantly increased insulin pharmacological availability, to 2.3%. A morphological study did not reveal any significant alteration of the rat intestinal mucosal integrity after exposure to 5 mM SDS for 30 min.2+ transport.
Shao
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Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
Li
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Krishnamoorthy
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Chermak
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Mitra
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AK
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002918:Chymotrypsin / Q000378:metabolism*; D002942:Circular Dichroism; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013501:Surface-Active Agents / Q000737:chemistry* / Q000494:pharmacology; D013552:Swine
D001786:Blood Glucose; D007328:Insulin; D013501:Surface-Active Agents; D002918:Chymotrypsin