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The Pharmacokinetics of Pulmonary-Delivered Insulin
Reference to this topic of inhaled insulin versus injectable insulin, pre-clinical studies are animal-based, and they have been carried out with the aim of understanding the pharmacology and disposition of inhaled insulin (Heise et al. 2005, p. 92). These pre-clinical animal-based studies investigate the effectiveness and safety of inhaled insulin in comparison to insulin administered through the standards routes, especially subcutaneous injection. All the preclinical studies discussed below support the effective and safe use of inhaled insulin. The pre-clinical study by Wigley et al. (1971) indicated that the provision of aerosol insulin was associated with reduced blood glucose levels from 150 to 90 mg/100ml within a period of two hours. The biological potency of inhaled insulin was well received by the rabbits because unlike the rabbits that received 20 units of regular insulin and died; those receiving aerosolized insulin did not suffer from adverse effects.
Wigley et al. (1971) had suggested that more studies should be conducted to develop strategies of increasing bioavailability of insulin aerosols. Studies by Colthorpe et al. (1992) and Sakr (1996; 1992) aimed at investigating ways of increasing insulin aerosol bioavailability. The use of gamma scintigraphy indicated that aerosolized insulin is correlated with penetration index. In contrast to instilled insulin that had a penetration index of 0.32, aerosol insulin had a penetration index of 1.52. In addition, compared to instilled insulin, aerosol insulin had a 10-fold higher bioavailability. The detected discrepancies could be attributed to differences in the distribution of instilled insulin (central deposition) in comparison to the uniform distribution of aerosol insulin. Sakr (1996; 1992) compared the bioavailability of aerosol insulin compared to intravenous insulin, and the results indicated a higher bioavailability for aerosol injection despite the fact that almost 30% of the nebulized insulin was retained in the nebulizer and around the rabbits nasal areas (1992, p. 6). In a study by Pillai et al. (1996) on rhesus monkeys, aerosol insulin was well tolerated and pulmonary functioning was normal.
Early studies conducted on human subjects have shown that inhaled insulin has similar beneficial effects as injectable insulin without producing any negative side effects. In their review, Patton, Bukar & Nagarajan (1999) indicated that inhaled insulin significantly lowers blood glucose, and it is absorbed without the need of penetration enhancers. An emerging issue is on the varied dosing of aerosol insulin, but this has been deemed to yield equivalent and even better results than subcutaneous injection. Heinemann, Traut & Heise (1997); Heinemann et al. (2000) and Kaptiza et al. (2003) have also indicated that the use of inhaled insulin is beneficial in controlling blood glucose because glucose infusion rate was more rapid when using inhaled insulin than when using injectable insulin. As a result, the use of inhaled insulin was associated with earlier attainment of maximal metabolic response, in comparison to subcutaneous injection. In a study conducted by Laube, Benedict & Dobs (1998), the time taken before peak insulin levels could be realized was the same for both subcutaneous injection and inhaled insulin. However, bioavailability of insulin and the average deposited drug was higher for inhaled insulin versus injectable insulin. A lot of studies have indicated that some nebulized aerosol insulin is lost due to retention in the nebulizer, but there are differences, in different studies, in the quantification of lost insulin that could be attributed to variation in dosing. Heinemann & Heise (2004), for example, showed that inhaled insulin has a biopotency of only 10%, suggesting a loss of 90%. Pfützner et al. (1998) have highlighted other reasons, other than the ones aforementioned, for the loss of inhaled insulin being the degradation of insulin by macrophages and peptidases in the alveoli, as well as the exhalation of the smaller particles of the insulin. This loss has led to the development of standard doses of inhaled insulin that range from 1.0 to 2.5 U/kg (Brunner et al. 2001; Jendle & Karlberg 1996).
References
Brunner, G, Balent, B, Ellmerer, M, Schaupp, L, Siebenhofer, A, Jendle, J, Okikawa, J, & Pieber, T 2001, Dose-response relation of liquid aerosol inhaled insulin in type I diabetic patients, Diabetologia, vol. 44, pp. 305-8.
Colthorpe, P, Farr, S, Taylor, G, Smith, I, & Wyatt D 1992, The pharmacokinetics of pulmonary-delivered insulin: a comparison of intratracheal and aerosol administration to the rabbit, Pharmaceutical Research, vol. 9, pp. 764-8.
Heinemann, L, & Heise, T 2004, Current status of the development of inhaled insulin, Br J Diabetes Vasc Dis, vol. 4, pp. 295-301.
Heinemann, L, Klappoth, W, Rave, K, Hompesch, B, Linkeschowa, R, & Heise, T 2000, Intra-individual variability of the metabolic effect of inhaled insulin together with an absorption enhancer, Diabetes Care, vol. 23, pp. 1343-47.
Heinemann, L, Traut, T, & Heise, T 1997, Time-action profile of inhaled insulin, Diab Med, vol. 14, pp. 63-72.
Heise, T, Kaptiza, C, Hompesch, M, & Heinemann, L 2005, Inhaled insulin as alternative delivery system for subjects with diabetes-A literature review, Av Diabetol, vol. 21, no. 2, pp. 91-102.
Jendle, J, & Karlberg, B 1996, Intrapulmonary administration of insulin to healthy volunteers, J Intern Med, vol. 240, pp. 93-8.
Kapitza, C, Heise, T, McGovern, M, Cefali, E, Buchwald, A, & Heinemann, L 2003, Time-action profile of a new pulmonary insulin applied with a metered-dose inhaler, Diabetes, vol. 52, suppl. 1, A91.
Laube, B, Benedict, G, & Dobs, A 1998 Time to peak insulin level, relative bioavailability and effect of site of deposition of nebulized insulin in patients with non-insulin dependent diabetes mellitus, J Aerosol Med, vol. 11, pp. 153-73.
Patton, J, Bukar, J, & Nagarajan, S 1999, Inhaled insulin, Adv Drug Deliv Rev, vol. 35, pp. 235-247.
Pillai, R, Hughes, B, Wolff, R, Heissermann, J, & Dorato, M 1996 The effect of pulmonary delivered insulin on blood glucose levels using two nebulizer systems, J Aerosol Med, vol. 9, pp. 227-40.
Pfützner, A, Heise, T, Steiner, S, Heinemann, L, & Rave, K 2000, Inhaled technosphere/insulin shows a low variability in metabolic action in type 2 diabetic patients [abstract], Diabetes, vol. 49, suppl. 1, A121.
Sakr , F 1996, Pharmacokinetics of pulmonary nebulized insulin and its effect on glucose tolerance in streptozotocin-induced diabetic rabbits, Int J Pharm, vol. 128, pp. 215-222.
Sakr, F 1992, A new approach for insulin delivery via the pulmonary route: Design and Pks in non-diabetic rabbits, International J Pharmaceutics, vol. 86, pp. 1-7.
Wigley, F, Londono, J, Wood, S, Shipp, J, & Waldman, R 1971, Insulin across respiratory tract mucous by aerosol delivery, Diabetes, vol. 20, pp. 552-6.
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