Prodrug Approaches To Extending Drug Activity In The Lung

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Most of the research centered on the targeting of drugs by the prodrug approach has been carried out on b2 stimulants structurally related to isoproterenol and similar drugs. The basic approach has been to esterify the catechol functions of isoproterenot to achieve better uptake in lung tissues of the resulting inactive lipophilic drug, which may then be metabolically cleaved by lung esterases to release the active parent compound [124,125]. In addition, esterification of the catechol function acts to protect the drug from deactivation by metabolic

Example Prodrug

16 a-BjdroiyprodniftOlcBe

Figure 6 Stereoselective metabolism of budesonide.

16 a-BjdroiyprodniftOlcBe

Figure 6 Stereoselective metabolism of budesonide.

conjugation. The elimination of cardiovascular side effects using this approach depends on the preferential uptake of the prodrug by the lung and the greater esterase activity in lung tissue relative to heart tissue. However, prolonged therapeutic effect may also be obtained simply by increasing drug residence time in the body through reduced renal clearance. This can be achieved by conjugation of the drug to form a lipophilic prodrug containing a slowly hydrolyzable linker group (e.g., a carbamate) [126].

A few drugs have been investigated that are members of this class (50-51). Bitolterol (50a) is the di-b-toluolyl ester of N-t-butylarterenol (50b) and is an effective long-lasting bronchodilator when given by intravenous injection, aerosol, or intraduodenal administration [127]; it is rapidly hydrolyzed after oral administration. Although the improved activity of this compound compared to the parent compound was thought to be due to its avid uptake by the lung followed by slow hydrolytic release of the active drug, recent lung perfusion studies in rabbits have shown that this is not the case [128]. These studies indicate rapid pulmonary hydrolysis of prodrugs such as bitolterol; however, it was pointed out the rabbit lung has greater esterase activity than that of dogs or humans. Nevertheless, it is hard to rationalize that the effect of the drug persists long after any drug remains in the lung. The drugs ibuterol (51a) and bambuterol (51b) are further examples of pulmonary prodrugs. Ibuterol (51a) is the di-isobutyryl ester of the resorcinol function of terbutaline (51c). After inhalation, ibuterol is three times as effective as terbutaline in the inhibition of bronchospasm [129]. Five minutes after inhalation, ibuterol has been shown to exhibit a greater pulmonary pharmacological effect or potency than does terbutaline when administered by this route.

Studies have shown that ibuterol is absorbed more rapidly than terbutaline after administration to the lung but that at all time points both lung and serum terbutaline concentrations were higher after terbutaline administration [130]. Thus, it appears that the prodrug ibuterol exhibits a greater pulmonary pharmacological effect or potency than does terbutaline when administered by inhalation.

Bambuterol (51b), the bis-N-N-dimethylcarbamate of terbutaline, produces a sustained release of terbutaline, a result of the slow, mainly extrapulmonary hydrolysis of the carbamate linkage. Unfortunately, because of its poor metabolism in the lung, it is not effective by the inhalation route. But it has been reported to yield good oral results and can be administered at much less frequent intervals than terbutaline [131]. In fact, bambuterol has been approved for treatment of asthma in almost 28 countries, in oral tablets as the hydrochloride salt. Bambuterol is stable to presystemic elimination and is concentrated by lung tissue after absorption from the gastrointestinal tract. The prodrug is hydrolyzed to terbutaline primarily by butyryl cholinesterase, and lung tissue contains this metabolic enzyme. Bambuterol is also oxidatively metabolized to products that can be hydrolyzed to terbutaline [132]. Bambuterol displays high first-pass hydrolytic stability and is only slowly hydrolyzed to terbutaline; hence, it can be administered orally, as infrequently as once a day. Bambuterol and its metabolites appear to be preferentially distributed to the lung, where an advantageous distribution and metabolism to active drug occurs. Thus, the prodrug is able to generate adequate concentrations of terbutaline levels in the lung. It has been reported that bronchodilator effects at low dosage are greater than can be predicated by plasma concentrations of terbutaline [133]. This may explain the significantly reduced systemic side effects compared to other oral bronchodi-lators. A study [134] postulated that several explanations can account for the disparity between plasma levels and drug effects as observed for several of the pulmonary products; that is, (a) the prodrug is metabolized in lung to an unknown but potent and long-acting pharmacological agent, (b) the prodrug releases small amounts of the parent drug at sites in lung from which its does not readily efflux, and (c) small amounts of the prodrug not reflected by bulk concentrations of prodrug in lung or plasma may sequester specific sites in the lung.

A related approach to the design of prodrugs of terbutalaine is the cascade ester approach. In this design, the phenolic functions of terbutaline are esterified with 4-0-(2,2-dimethylpropionyloxy)-benzoic acid (51d). The cascade effect is postulated initially to involve cleavage of the pivolate ester and 0 conjugation during first-pass metabolism to protect the terbutaline phenolic groups; the subsequent hydrolysis of the hydroxybenzoyl link would, therefore, be delayed. However, data indicate that in dogs and humans this type of prodrug has no advantage over bambuterol, because both compounds are very slowly hydrolyzed in plasma, and significant plasma concentrations of the monoester of these prodrugs are not seen in vivo [134]. Another related approach to the design of prodrugs to target alveolar macrophages has been carried out using microspheres as a primary carrier of the prodrug [135].

The drug isoniazid has been used in this fashion, it was structurally modified into an ionizable form suitable for hydrophobic ion pairing. The charged prodrug, sodium isoniazid methanesulforate, was then ion paired with hydrophobic cations, such as alkyltrimethyl ammonium ion. The drug was then encapsulated into polymeric microspheres to form hydrophobic ion-paired complexes. The ion-pair complex and polymer were coprecipitated using supercritical fluid methodology [136].

POTENTIAL USEFULNESS OF CELL MEMBRANE-BOUND ENZYME SUBSTRATES AND INHIBITORS, AND CELL MEMBRANE-BOUND RECEPTOR AGONISTS AND ANTAGONISTS AS DRUG CARRIERS WITH LUNG SPECIFICITY

Ranney [137,138] postulated that pulmonary clearance of drug molecules from the systemic circulation may be achievable by targeting selective binding sites on the pulmonary endothelial membrane. In this regard, a possible strategy may be to link drug molecules to ligands that have high affinity for these endothelium binding sites. For example, several hydrolytic enzymes, such as peptidases and phosphorylases, are known to be located on the surface membrane of lung epithelium and endothelium [139-142]. Such enzymes may be targetable by designing drug conjugates with appropriate substrates or tight-binding inhibitors (i.e., nonhydrolyzable substrates). Table 1 illustrates the number and types of peptidase enzymes that are known to be bound to pulmonary endothelial or epithelial membranes. The existence of a selection of membrane-bound epithelial enzymes may well be useful in designing appropriate drug conjugates with multiple ligands for these enzyme-active sites as bioadhesive targeting agents. Ranney [137] pointed out that ligands that bind multiple active sites may be more useful as drug carriers on the grounds that populations of some receptors may be significantly decreased or lost entirely in some diseased states, for example, membrane-bound dipeptidyl aminopeptidase (angiotensin-converting enzyme), and phosphodiesterase enzymes (PDEs). The cyclic nucleotide PDEs comprise a family of enzymes whose role is to regulate cellular levels of the second messengers, cAMP and cGMP, by hydrolyzing them to inactive metabolites. PDE IV is the predominant PDE isozyme in inflammatory and immune cells and thus regulates a major pathway of cAMP degradation. Elevation of cAMP levels supresess cell activation in a wide range of inflammatory and immune cells [143]. The attraction of PDE IV inhibition as a therapy for asthma derives from the potential of selectively elevating cAMP levels in the airway smooth muscles and the inflammatory response [144].

Table 1 Membrane-Bound Enzymes on Lung Endothelial and Epithelial Cells

Enzyme

Location

Dipeptidyl carboxypeptidase

Endothelial membrane

(ACE) (EC 3A.15.1)

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