Lipophilic drug absorption prodrug approach

On the other hand, highly lipophilic compounds, such as hormones, can be solubilized via the prodrug approach. For example, the rate of transdermal absorption of the highly lipophilic drug, testosterone, was enhanced over 50-fold by forming water-soluble, yet lipophilic, prodrug ester.f The prodrug testoster-onyl-4-dimethylaminobutyrate was found to penetrate human skin tissue, in vitro, 54 times faster than... 

The prodrug approach 2 has been resorted to in some instances to improve the ocular/systemic absorption ratio, as in the case of dipivalylepinephrine (Dipivefrin, DPE), a lipophilic prodrug of epinephrine (EP), an antiglaucoma topical drug. The majority of topical EP, administered as a 2% solution, enters the systemic circulation, as a result of systemic absorption through the nasal mucosa, and has been reported many times to produce systemic a- and p-adrenergic symptoms. DPE has no apparent systemic effect, because the enzymatic release of EP occurs most efficiently in the cornea, which is better penetrated by the more lipophilic DPE. The rationale for the realization of prodrugs is illustrated in Fig. 8. 

Another approach to overcome the absorption problems of lipophilic molecules is the synthesis of a prodrug a derivative of an active parent compound, which undergoes transformation in the body to form the free drug. Two diverse rationales can be applied in this approach (1) to form a prodrug complex that has decreased lipophilicity in comparison to the free drug, or (2) to make a prodrug with elevated lipophilicity. 

When the transdermal penetration of a drug is inadequate to achieve and maintain a plasma concentration above the minimum therapeutic concentration required to produce the desired effect, a lipophilic prodrug that will be metabolized in the epidermis to the active drug could be used in the development of a controlled-release transdermal delivery system. This approach has been applied to estradiol esters (diacetate and valerate) which are rapidly converted by esterases in the skin tissue to estradiol (Chien et al, 1985). The prodrug serves to increase the transdermal bioavailability of the active drug to which it is converted by metabolism (generally ester hydrolysis) during the percutaneous absorption process. 

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