Lipophilicity ester prodrugs

Hansen LB, Christrup LL, Bundgaard H (1992) Enhanced delivery of ketobemi-done through porcine buccal mucosa in vitro via more lipophilic ester prodrugs. Int J Pharm 88 237-242... 

Even more complex potential prodrugs of indomethacin were examined, namely its limonenyl, perillyl, bomyl, and menthyl esters, i. e., terpenoid derivatives [21]. These highly lipophilic esters showed rapid enzymatic hydrolysis, and the limonenyl prodrug assayed in humans had an interesting delayed and sustained cutaneous anti-inflammatory activity. 

Loftssona et al. [98] found that with increases in the concentration of HP-(3-CD, the flux of a hydrophobic drug arachidonylethanolamide increased. Later, Tirucherai and Mitra [99] found that HP-(3-CD could also enhance the corneal permeation of the lipophilic drug ganciclovir dibutyrate (acyl ester prodrug of ganciclovir). Aktas [100] also found that addition of HP-(3-CD to the simple aqueous solution of pilocarpine nitrate increased the permeation of pilocarpine nitrate by four times in an in vitro permeability study using isolated rabbit cornea. 

The design of salt forms of prodrugs is associated most commonly with solubility and stability enhancement in various dosage forms. Ester prodrugs often are converted to salts to provide the desired balance of hydrophilic/lipophilic properties.45... 

A good example of a transdermal prodrug is an alkyl ester prodrug of naltrexone designed to improve lipophilicity of the parent compound and increase its delivery rate across the skin. The mean naltrexone flux from the prodrug-saturated solutions exceeded the flux of naltrexone base by approximately two- to seven-fold. 

Ester prodrugs are employed to enhance membrane permeation and transepithelial transport of hydrophilic drugs by increasing the lipophilicity of the parent compound, resulting in enhanced transmembrane transport by passive diffusion. For example, pivampicillin, a pival-oyloxymethyl ester of ampicillin, is more lipophilic than its parent ampicillin and has demonstrated increased membrane permeation and transepithelial transport in in vivo studies.103... 

Although amino acid 1 is a potent inhibitor of CMP-KDO synthase (Figure 36.21), a key enzyme in the biosynthesis of the lipopolysaccharide of Gram-negative bacteria, it is unable to reach its cytoplasmic target and is therefore inactive as an antibacterial agent. Simple lipophilic esters are not useful to enhance the delivery of amino acid 1 since they are not cleaved by the bacteria. On the other hand, double prodrug 3 has been found to solve the problem. ... 

Amsberry and Borchardt" " have applied Cain s cascade concept to prepare lipophilic polypeptide prodrugs. The amine functionality of the polypeptide is coupled to 2 -acylated derivatives of 3-(2, 5 -dihydroxy-4, 6 -dimeth-ylphenyl)-3,3-dimethylpropionic acid (Figure 36.23). Under simulated physiological conditions the parent amine is regenerated in a two-step process enzymatic hydrolysis of the phenolic ester, followed by a non-enzymatic intramolecular cyclization, leading to the release of the free amine (polypeptide) and a lactone. 

Oseltamivir (GS 4104, 4a), developed by Gilead/Hoffmann-LaRoche and marketed as Tamiflu , is the first commercially available orally active, noncarbohydrate mimetic of Zanamivir (3) [49-51]. It is based on a cyclohexene framework with a lipophilic moiety replacing the glycerol side chain of Zanamivir (3). It is orally administered as an ethyl ester prodrug GS 4104 (4a), which—upon absorption in the gastrointestinal tract—undergoes rapid enzymatic conversion by the action of... 

The lipophilicity of a glucocorticoid can be enhanced by esterification with lipophilic acids. Doing so results in a number of effects, including increasing the log P, which provides local activity with less systemic absorption and decreased side effects. The fact that C-21 lipophilic esters are prodrugs means that they have a longer duration of action. They also have a slower onset, because the lipophilic esters generally are bulky and retard hydrolytic enzymes. 

These lipophilic prodrugs can be administered orally to treat a variety of conditions, by inhalation to treat asthma and COPD, and topically to treat various types of dermatitis. When administered orally, their longer duration of action means that they can be given less frequently, which often results in better compliance. Figure 44.30 shows the structures of the most common C-21 lipophilic esters found on commercially available glucocorticoids. 

Stereoselectivity in the metabolism and percutaneous permeation, related to skin enzymatic activity, was reported for several compounds [23-28]. Stereoselectivity in permeation and cutaneous hydrolysis of several ester prodrugs of propranolol through hairless mouse skin was investigated [23]. The authors reported the stereoselective hydrolysis of propranolol prodrugs that is notably biased towards the R-isomer, which resulted in the enantioselective permeation. The lipophilicity of prodrugs, expressed as the partition coefficients, was found to affect the apparent skin permeability coefficients. The more lipophilic prodrugs readily entered into the stratum corneum, but their clearance into hydrophilic deeper strata (epidermis and dermis), where drug hydrolysis takes place, was much less effective. Unlike S-isomers, the R-isomers of propranolol esters were entirely hydrolyzed in epidermis and freely crossed the dermis strata. 

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