Pulmonary bioavailability

H. Derendorf, G. Hochhaus, S. Rohatagi, H. Mollmann, J. Barth, and M. Erdmann, Oral and pulmonary bioavailability of triamcinolone acetonide, J. Clin. Pharmacol. 35 302 (1995). 

L. Borgstroem, and M. Nilsson, A method for determiniation of the absolute pulmonary bioavailability of inhaled drugs Terbutahne, Pharm. Res. 7 1068 (1990). 

Nessel CS, Amoruso MA, Umbreit TH, et al. 1992. Pulmonary bioavailability and fine particle enrichment of 2,3,7,8-tetrachlorodibenzo-p-dioxin in respirable soil particles. Fundam Appl Toxicol 19(2) 279-85. 

Hydroxy propyl-p-cyclodextrin and especially dimethyl-p-cyclodextrin have been shown to enhance the pulmonary bioavailability of insulin in rats, and indications were found of a relatively low acute mucotoxicity. " ... 

GIT, is considered to be lost from the absorption site, as is metabolic clearance and sequestration in various cell types and membranes (72,14). It is clear from Scheme I that the relative rates of the various processes will define the bioavailable fraction of the dose and understanding those factors which control pulmonary absorption kinetics is obviously the key to enhancing bioavailability via the lung. In a recent book (75) the molecular dependence of lung binding and metabolism was considered alongside the parallel processes of absorption, clearance and dissolution in the lung (14). Some key features of this work will be repeated as it relates to the systemic delivery of polypeptides. 

A Adjei, J Garren. Pulmonary delivery of peptide drugs effect of particle size on bioavailability of... 

The inhalation route for administering drugs into the pulmonary system for treatment of respiratory diseases eliminates many bioavailability problems such as plasma binding and first-pass metabolism, which are encountered in parenteral or oral administration. Consequently, a small inhalation dose is adequate for achieving... 

Tronde A, Norden B, Marchner H, Wendel AK, Lennernas H, Bengtsson UH (2003) Pulmonary absorption rate and bioavailability of drugs in vivo in rats structure-absorption relationships and physicochemical profiling of inhaled drugs. JPharmSci 92 1216-1233. 

Proteolytic enzymes in the respiratory mucosa play important role(s) in the regulation of lung inflammation and remodelling [123, 124], Pulmonary proteolytic enzymes, however, also comprise one of the barriers which pulmonary-administered protein/peptide drugs have to overcome in order to achieve adequate bioavailability [125]. Intriguingly, the pulmonary enzymatic barrier is an aspect that has been little investigated and is poorly understood. Inconsistencies in the data available to date are most likely a result of the use of different techniques (e.g., PCR, immunotechniques and enzyme activity assays), different species and different cell (pheno)types, for example primary cells vs. cell lines. 

An ideal in vitro model for the characterization of aerosol formulations would incorporate cell types from various regions of the lung (tracheal, bronchial, and alveolar) and would facilitate simulation of deposition mechanisms by impaction, sedimentation, and diffusion of a high-metered singlebolus inhalation. In the future, such systems may reduce the need for animal studies and may offer to correlate in a predictive way the results from such in vitro tests to clinical bioavailability data after pulmonary drug delivery in vivo. 

Liposomes were formed from 1,2-dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Choi) and the effect of liposomal entrapment on pulmonary absorption of insulin was related to oligomerization of insulin (Liu et al. 1993). Instillation of both dimeric and hexameric insulin produced equivalent duration of hypoglycemic response. However, the initial response from the hexameric form was slightly slower than that from dimeric insulin, probably due to lower permeability across alveolar epithelium of the hexameric form caused by larger molecular size. The intratracheal administration of liposomal insulin enhanced pulmonary absorption and resulted in an absolute bioavailability of 30.3%. Nevertheless, a similar extent of absorption and hypoglycemic effects was obtained from a physical mixture of insulin and blank liposomes and from liposomal insulin. This suggests a specific interaction of the phospholipid with the surfactant layer or even with the alveolar membrane. 

A composition based on diketopiperazine derivatives (3,6-bis (N-fumaryl-N-(n-butyl) amino-2, 5-diketopiperazine) has been investigated as a pulmonary drug delivery system, termed Technospheres (Pharmaceutical Discovery Corp., Elmsford, NY) (Pohl et al. 2000 Steiner et al. 2002). The diketopiperazine derivatives self-assemble into microparticles at low pH with a mean diameter of approximately 2 pm. During self-assembly, diketopiperazine derivatives microencapsulate peptides present in the solution. Insulin incorporated in diketopiperazine derivatives (TI) was administered to five healthy humans by the use of a capsule-based inhaler with a passive powder deagglomeration mechanism. Relative and absolute bioavailability of TI in the first 3 hours (0-180 min) were 26 12% and 15 5%, and for 6 hours (0-360 min) 16 8% and 16 6%, respectively (Steiner et al. 2002). The time to peak action for glucose infusion rates was shorter with both IV (14 6 min) injection and inhalation (39 36 min), as compared to SC administration (163 25 min). This rapid absorption of insulin would be beneficial for diabetic patients who need to rapidly affect their glucose levels. 

By the use of a breath-powered unit dose dry powder inhaler, which was adapted to the physical properties of TI, relative bioavailability was 50% for the first 3 hours and 30% over the entire 6-hour period in 12 healthy volunteers (Pfutzner et al. 2002). However, although the studies demonstrated pulmonary administration of TI has the advantages of fast onset of action, short duration of action, and lower variability over the SC injections of insulin no attempt has been made to compare pulmonary administration of insulin alone with the same inhaler device. This method of encapsulating biomacromolecules has some advantages and must be considered when electing to deliver a molecule. 

---