It has been known for several years that the lung is capable of active uptake of a number of endogenous and exogenous compounds. These include the neurotransmitters norepinephrine and 5-hydroxytryptamine, which are sequestered by lung endothelial cells [105,106], and the lung toxins parquat  and 4-ipomeanol . Paraquat is selectively accumulated in type II alveolar cells by an energy-dependent process, whereas the site-specific toxicity of 4-ipomeanol appears to be due to the selective uptake by Clara cells that, because of the presence of cytochrome P-450 PB-B activity, bioactivates the molecule into a toxic species. In the case of the neurotransmitters norepinephrine and 5-hydroxytryptamine, both compounds have been shown to be avidly sequestered by the canine lung; pulmonary extraction percentages after intravenous injection in the nanmolar range into the pulmonary artery amount to 70% and 50%, respectively . Although it is not clear what structure-activity relationships govern the uptake of these compounds into lung endothelia, a possible strategy for lung targeting might be to chemically conjugate a drug molecule with either 5-hydroxytryptamine or norepinephrine or, better still, to conjugate the drug to pharmacologically inactive metabolites or analogues of these neurotransmitters that still retain the selective lung uptake properties. Generally, it is recognized that the lung has a mechanism for the high-affinity uptake of amines that are protonated at physiological PH and that also possess a hydrophilic moiety in their structure. In most cases, such compounds are metabolized by lung tissue and, therefore, do not accumulate. However, a select number of amines of this type that are resistant to lung metabolism have been observed to accumulate in lung tissue for prolonged periods [109-111]. It is important to note that, generally, quarternary ammonium compounds, which are unable to dissociate into an unionized form, are not effectively taken up by lung tissue, although a notable exception is paraquat. Thus, the equilibrium between ionized and unionized drug is important and suggests that the unionized hydrophobic form may be required for transport, whereas the protonated form is necessary for binding to anionic sites in lung tissue. The exact nature of these anionic sites is not known, although they may be negatively charged phospholipid molecules, which are known to exist in high concentrations in lung tissue, Also, the uptake mechanism may involve a mechanism of preferential pH partitioning of the amine species into the lung or the involvement of a lipophilic ion-pair transport process. Several studies showed that lipophilic cationic drugs bound to anionic sites in the lung can be displaced by other lipophilic cationic drugs .
The nature of the uptake site, or the involvement of any particular lung cell type in the uptake process, is as yet unknown. It seems possible that drugs conjugated to lipophilic amines of the types described previously can undergo efficient pulmonary targeting. Several amines may be useful in this respect; that is, the compounds chlorphentermine, amiodarone, desethylarniodarone, and desmethylimipramine all exhibit high affinity to lung tissue. Thus, drugs that normally have poor access to the lung may be targeted to this tissue through appropriate chemical combination of an available functional group (i.e., OH or COOH) with the amino function of the carrier molecule (Fig. 3). Of course, the success of this drug design also depends on the ability of lung tissue to release the bound drug from the carrier molecule by some enzymic process; in other words, the approach basically would have to be a targeted prodrug design. Kostenbauder and Sloneker  recently investigated the usefulness of chlorphentermine as a carrier for lung targeting by conjugating it to an unspecified pulmonary drug to give a conjugate of general structure 49 (Fig. 4). In this design, the released carrier molecule is anionic and would be predicted to be rapidly washed out of the lung. Isolated, perfused lung experiments indicated that the prodrug was able to displace chlorphentermine from lung-binding sites and that subsequent prodrug hydrolysis occurred with carrier wash out from the lung. However, the in vivo activity of the prodrug could not be evaluated because of its extreme toxicity.
It has been argued that, because many strongly basic lipophilic amines have been found to exhibit high uptake but only very few truly sequester in the lung and exhibit slowly effluxable pools in vivo, prodrug design should focus on simply achieving high concentrations of prodrug in the lung rather than developing conjugates that would establish amine effluxable pools in lung tissue . In this respect, simple alkyl amines, such as octylamine, could be used because these compounds show high affinity for lung tissue, which correlate with their octanol-water partitioning. This approach has the added advantage of keeping conjugate structures as simple as possible to avoid pharmacological problems.
Of interest are the b2 agonists salmeterol (1) and formoterol (3), both of which exhibit plasma half-lives similar to that of salbutamol (2), although the latter compound has a much shorter duration of action. Thus, in these cases,
replacing the N-t-butyl group in salbutamol with a highly lipophilic group results in a drug with high affinity for lung tissue and long duration of drug action. It is puzzling, however, that the bronchodilator effects of these drugs are still present even when the drug is no longer detectable or, indeed, even predictable, from elimination half-lives, in plasma [114,115]. This observation may relate to the possible retention in lung of a microfraction of the absorbed dose, presumably in the vicinity of the drug-receptor site.
Salmeterol (1) was designed by modifying salbutamol to obtain a drug with much greater affinity for its receptors because of increased "exoreceptor" binding  and, consequently, a persistent localization in the vicinity of b2-receptor. However, there is no evidence for this hypothetical mechanism, and the alternative suggestion that the drug is able to diffuse into the airway epithelium, which then acts as a reservoir for the drug, appears to be a more likely mechanism .
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