Epinephrine, dipivaloyl derivative

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

Because of the high aqueous solubility of epinephrine, its usefulness in the treatment of glaucoma is limited. The dipivaloyl derivative, with its higher lipid solubility has a far greater ability to pass through the lipoidal barrier into the cornea, where it is presumably hydrolyzed back to the parent compound. The clinical result of using the pro-drug in this case is a 100-fold increase in therapeutic effectiveness. 

Starting from hydroxylic derivatives, high lipophilicity can simply be obtained by esterification with lipophilic carboxylic acids. Dipivaloyl-epinephrine, for example (Figure 36.5), crosses the cornea and is used in the treatment of... 

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