Methods To Assess Pharmacokinetic And Dynamic Properties Of Inhalation Drugs

Earlier we described how pharmacokinetic and dynamic properties of inhaled drugs are relevant for pulmonary selectivity. The assessment of pharmacokinetic and dynamic properties is consequently relevant for drug development and clinical practice. This section reviews some of the relevant techniques for assessing such properties. The available tools range from cell culture or isolated lung perfusion models to mucociliary clearance analysis, imaging techniques, and in vivo pharmacokinetic and dynamic analysis of the inhaled drug.

Cell Culture Methods to Assess Drug Transport

Cell culture models to evaluate the pulmonary fate of inhaled drugs have not been used extensively for characterizing inhalation drugs. However, this technique is promising and will be briefly discussed. This section focuses on airway and alveolar epithelial models using cell lines and primary cell culture methods.

Airway Epithelial Cell Cultures

Primary cultures of airway epithelium have been described for many animal species, including humans [53]. These primary epithelial cell cultures have been demonstrated to be useful in investigating the influence of lipophilicity and molecular size on epithelial permeability as well as for investigating mechanisms of absorption. Three of the most promising human bronchial cell lines used as absorption models are 16HBE14o, Calu-3, and BEAS-2B [54].

Alveolar Epithelial Cell Cultures

The primary alveolar epithelial cell cultures [55,56] arises from the alveolar type II cells. The advantage of these cell cultures is that they differentiate into monolayers of cells with morphology similar to Type I cells. Transepithelial delivery of protein, peptides, and macromolecules such as dextran has been evaluated using A549 cells, a lung carcinoma cell line, as a model of the alveolar epithelium. Although these cell culture models are associated with several drawbacks [55], such as being unable to mimic in vivo clearance mechanisms, they do serve as a valuable tool for assessment of drug transport.

Isolated Lung Perfusion Models

Isolated lung perfusion models have been instrumental in assessing the pulmonary fate of inhaled drugs by employing lungs of rabbits, rats, and guinea pigs [57-60]. These models permit investigation of pulmonary dissolution, absorption, lung tissue binding, transport phenomena, and metabolism while maintaining the physiological properties of the lung. The drug is delivered into the ventilated lung either by intratracheal injection or via a modified MDI. These experiments result in typical absorption profiles (drug absorbed as a function of time) of drug and its metabolites (if applicable; see Fig. 10). The isolated perfused lung was one of the models that indicated that a fraction of budesonide is captured in the lung. In addition, estimates of the mucociliary clearance (see next section) can be obtained.

Assessment of the Mucociliary Clearance of a Drug

Pulmonary clearance through the mucociliary transport is relevant for inhalation therapy, mainly for the upper portion of the lung. With more lipophilic drugs being used for inhalation therapy, incorporating the mucociliary clearance in the pharmacokinetic assessment of an inhalation drug is becoming more relevant, because the slow dissolution rate of these drugs makes them more vulnerable for mucociliary removal. As a matter of fact, some of the reported low systemic bioavailabilities of new inhaled steroids might be related to their high lipophilicity and slow dissolution rates, because this provides enough time for the undissolved particles to be removed by the mucociliary transporter.

Mucociliary clearance has been routinely assessed using radioactive-labeling techniques [61]. This technique often involves monitoring mucociliary clearance of inhaled monodisperse 5-mm particles of polystyrene or particles generated from 99mTc-labeled iron oxide [62]. However, these well-established techniques do not permit direct monitoring of drug particles. Recently, Byron and

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