Absorption, drug ester prodrugs

Heylen, P., van den Mooter, G., Kinget, R., Drug absorption studies of prodrugs esters using the Caco-2 model evaluation of ester hydrolysis and transepithelial transport, Int. J. Pharm. 1998, 166, 45-53. 

He X, Sugawara M, Kobayashi M, Takekuma Y, Miyazaki K (2003) An in vitro system for prediction of oral absorption of relatively water-soluble drugs and ester prodrugs. Int J Pharm 263 35 14... 

Beaumont, K., et al. 2003. Design of ester prodrugs to enhance oral absorption of poorly permeable compounds Challenges to the discovery scientist. Curr Drug Metab 4 461. 

Sinko, P. J., and Balimane, P. V. Carrier-mediated intestinal absorption of valacyclovir, the L-valyl ester prodrug of acyclovir I. Interactions with peptides, organic anions and organic cations in rats. Biopharm. Drug Dispos. 19(4) 209-217, 1998. 

Subcellular localization studies have identified P-450-dependent monooxygenase activity in adult hairless mice sebaceous glands. Phase II conjugation pathways have also been identified in skin. Extracellular enzymes including esterases are present in skin, which has been utilized to formulate lipid-soluble ester prodrugs which penetrate the stratum corneum and then are cleaved to release active drug into the systemic circulation. Finally, co-administration of enzyme inducers and inhibitors modulate cutaneous biotransformation and thus alter the systemic toxicity profile. These metabolic interactions that occur in skin have attracted a great deal of research attention and clearly illustrate that skin is more than a passive barrier to toxin absorption. 

Ester prodrugs are used for a variety of reasons, not just for increasing the rate of absorption for a drug. For example, consider the structure of the antibiotic agent chloramphenicol ... 

In attempts to improve the oral activity of norfloxacin, prodrug techniques have been employed. In an initial approach, the (5-methyl-2-oxo-l,3-diox-4-yl)-methyl group, which had been shown previously to be effective in a novel ampicillin prodrug, was investigated as a promoiety [ 109]. However, although the ester (77) liberates norfloxacin in the presence of mouse blood, after oral administration to mice, it was found that the blood levels of norfloxacin achieved are lower (approximately with respect to Cmax) than those achieved upon oral administration of an equimolar dose of norfloxacin, itself. This observation has been assumed to be due to an instability of this ester prior to absorption rather than an inability to liberate the parent drug after absorption. 

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