Bioavailability prodrug approach

Prodrug approaches have been used to increase the oral bioavailabilities of cephalosporins. Ester prodrugs are formed by reversible esterification of the carboxyl group on these antibiotics [20], These prodrugs are more orally bio-... 

Overall, the prodrug approach is a well-established strategy to improve the bioavailability and targeting of pharmacophores, and is a vital component in the development of therapeutics and drug-delivery strategies. 

Despite excellent intrinsic potency, weak oral activity limited the in vivo activity of 218 d. Efforts to improve its oral bioavailability by a prodrug approach led to the preparation of two compounds with improved oral activity and bioavailability, the dioxolenonylmethanol ester BMS 184698 219 and the M-alkyl tetrazole prodrug 220, Eq. (88). 

Drug Discovery Today 7 25-27 Li AP (2004) In vitro approaches to evaluate ADMET drug properties. Curr Top Med Chem 4 701-706 Li W, Escarpe PA, Eisenberg EJ et al. (1998) Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071. Antimicrobial Agents and Chemotherapy 42 647-653 Los LE, Welsh DA, Herold EG et al. (1996) Gender differences in toxicokinetics, liver metabolism, and plasma esterase activity observations from a chronic (27-week) toxicity study of enalapril/diltiazem combinations in rats. Drug Metab Dispos 24 28-33... 

Bisphosphonates pamidronate and alendronate (the most active bisphos-phonates approved for clinical use) were converted into the peptidyl prodrugs prolyl-phenylalanylpamidronate [Pro-Phe-pamidonate (420)] and prolyl-phenylalanyl-alendronate [Pro-Phe-alendronate (421)]. It was shown that the bioavailability of bisphosphonates can be enhanced by using the peptide prodrug approach. The increased oral absorption of the prodrugs was reduced by an active carrier-mediated transport. ... 

Using microdialysis experiments the relative oral bioavailabilities of the compounds 34, 35, 11, 80, 12, 83 and 9 could be calculated. These data show that a compound with a catechol or a phenol possesses a low relative oral bioavailability (compounds 11, 80, 12 and 9). To circumvent such a low relative oral bioavailability a bioisostere of a phenol could be introduced or a prodrug approach could be applied. Compounds 34 and 35 are examples of a bioisosteric replacements and compound 83 is a prodrug of a catecholic or a phenolic 2-aminotetralin. Both types of compounds show an improved relative oral bioavailability, as compared to the... 

The prodrug approach thus has the potential to increase bioavailability, optimize elimination kinetics, and affect biodistribution. The approach has found broad application in many areas of the pharmaceutical industry and a more comprehensive review can be found in the book Prodrug Design and Synthesis by the late Prof. Bungaard (27). 

Several types of chemical derivatives have been studied for designing oral prodrugs. The purpose of the next section is to examine various approaches for obtaining oral prodrug forms which improve the absorption and bioavailability of the parent compound. 

AN Saab, LW Dihert, AA Hussain. Isomerization of cephalosporin esters Implications for the prodrug ester approach to enhancing the oral bioavailabilities of cephalosporins. J Pharm Sci 77(10) 906-907, 1988. 

The design of prodrugs that are activated by intramolecular reactions, i.e., prodrugs that are partly or completely activated without the need for enzymatic contribution, is an area of great current interest. As outlined in Chapt. 1, this approach can lead to a decrease in biological variability that facilitates the development of clinically useful prodrugs. One important condition, however, is that intramolecular catalysis should not be so fast that it results in poor bioavailability. 

As reviewed in this chapter, certain means can be utilized to improve the bioavailability of lipophilic drugs, whether by formulative approach or molecular changes strategies. These means present a number of attractive propositions to the scientist, ranging from an enhancement of drug dissolution and solubilization by lipid-based formulation, increased solubility via the synthesis of a prodrug, specific delivery to the intestinal lymphatics, and reduction in enterocyte-hepatic presystemic metabolism and efflux systems. 

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