Insulin bioavailability

Proteases occurring in the epithelial lining fluids are another source of variability in protein absorption from the lung. In the epithelial lining fluids proteases and peptidases do occur. Inhibition of proteases and peptidases with substances such as bacitracin or aprotinin might improve the bioavailability of proteins. For example bacitracin was shown to increase insulin bioavailability by a factor of 6.8 [3]. 

Chitosan microspheres were shown to enhance nasal bioavailability of several peptide drugs such as insulin and goserelin. A simple chitosan-insulin powder formulation provided about 20% of absolute insulin bioavailability in sheep [96], Improved bioavailability (of 44%, in rats) was obtained when insulin was loaded into chitosan microspheres prepared with ascorbyl palmitate as cross-linking agent [91]. Chitosan microspheres have also been shown to improve nasal goserelin absorption providing about 40% bioavailability relative to goserelin intravenous application [9],... 

Krauland et al. [93] prepared the microparticles with thiolated chitosan (chitosan-TBA chitosan-4-thiobutylamidine conjugate) intended for nasal peptide delivery. During the preparation process microparticles were stabilized by the formation of inter- and intramolecular cross-linking via disulfide bonds. Chitosan-TBA microparticles were characterized by improved swelling ability and displayed 3.5-fold higher insulin bioavailability compared to unmodified chitosan microparticles. 

J. P. (2006), Influence of deposition and spray pattern of nasal powders on insulin bioavailability, Int. J. Pharm., 310,1-7. 

Many papers have been published on the use and efficacy of absorption enhancers for nasal peptide and protein delivery. The enhancing effect of bile salt seemed dependent on its lipophilicity The bioavailability of gentamicin increased with increasing lipophilicity of trihydroxy bile salts (cholate > glycocholate > taur-ocholate), and the enhancement of nasal insulin bioavailability followed the rank order of deoxycholate, chenodeoxycholate, and cholate. However, most studies reported severe damage of bile salts to the mucosa. Deoxycholate had the most ciliotoxic effect, whereas taurocholate had the least ciliotoxic effect. In the case of dihydrofusidates, a dose-dependent increase in bioavailability was reported for peptides such as insulin. 

The presence of medium chain fatty acids and glycerides in food products has stimulated interest in their potential utility as absorption enhancers. Some fatty acids and glycerides have been shown to increase drug absorption under a variety of conditions, almost always in animals and in most cases after rectal dosing. However, some studies have yielded positive results after oral dosing. Oral insulin bioavailability was increased to 9-13% relative to IM administration by a mixture of sodium dodecanoate and cetyl alcohol. Aftiraxone absorption was enhanced by glyceryl-1-monooctanoate after oral, duodenal, and rectal administration to animals. 

Excess insulin may also arise as the result of increased insulin bioavailability or sensitivity. Changing the insulin species or formulation administered may induce hypoglycaemia by altering the pharmacokinetic properties of insulin and enhancing its efficacy. 

Steiner S, Rave K, Heise T, Harzer O, Flacke F, Pfiitzner A, Heinemann L. Technosphere /insulin bioavailability and pharmacokinetic properties in healthy volunteers. Diabetologia 43(Suppl. 1) 771, 2000. 

Insulin Bioavailability (Percent of Parenteral Availability) after Noninvasive Administration without Enhancer to Rats by Various Routes... 

Bioavailability of human insulin assessed from pharmacological data. After extravascu-lar administration only the time course governs the observed pharmacological effects. The pharmacological data was translated into theoretical plasma-concentration data using the PK/PD model. The results of the PK/PD analysis indicate that the doses administered can be accurately predicted from pharmacological data... 

Miyazaki, M., Mukai, H., Iwanaga, K., Morimoto, K., and Kakemi, M., Pharmacokinetic-pharmacodynamic modeling of human insulin validity of pharmacological availability as a substitute for extent of bioavailability, /. Pharni. Pharmacol., 53, 1235-1246, 2001. 

The enzymatic degradation of insulin was also shown to occur in the cytosol of alveolar cells, the pH optimum of the proteases being 7.4 [38]. To what extent intracellular proteases play a significant role in limiting the absorption of insulin is not clear, since the size of insulin likely allows paracellular transport over the alveolar epithelium. However, for proteins of higher molecular weight, that require transcellular transport, these proteases might certainly limit bioavailability. 

The bioavailability of the insulins is identical when given subcutaneously. The human insulins are slightly less antigenic than pork or beef insulins. Human insulin is the insulin of choice for patients with insulin allergy, insulin resistance, all pregnant patients with diabetes, and any patient who uses insulin intermittently. ... 

STDHF has also been shown to enhance intranasal delivery of insulin. The bioavailability of insulin (51 aa) formulated as a nasal drop or spray containing STDHF was 16% to 47% in healthy volunteers [22].The... 

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