Bioavailability prodrugs

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... 

Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071. Antimicrobial Agents and Chemotherapy,... 

In order to enhance the oral bioavailability of oximonam (104), a prodrug has been made by esterification of the carboxyl group with the t-butyl ester of hydroxyacetic acid (105). The product is prodrug gloximonam (106) [31], Gloximonam is efficiently converted to oximonam in the body by metabolic processes. 

Most ACE inhibitors are prodrugs, with the exceptions of captopril, lisinopril, and ceranapril. Prodrugs exert improved oral bioavailability, but need to be converted to active compounds in the liver, kidney, and/or intestinal tract. In effect, converting enzyme inhibitors have quite different kinetic profiles with regard to half time, onset and duration of action, or tissue penetration. 

Since the ANPs are only slowly taken up by the cells and poorly absorbed following oral administration, some efforts have been directed toward the development of prodrugs (esters) that would be better taken up by the cells. These efforts have yielded the bispivaloyloxymethyl [bis(pom)] derivative of PMEA (Fig. 6) [56]. Bis(pom)-PMEA shows a cellular uptake increased more than a hundredfold, as well as fivefold better oral bioavailability than the parent compound [57], Both PMEA (given intravenously) and bis(pom)-PMEA (given perorally) are now in clinical trials in patients with AIDS. 

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. 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

To reduce conjugative first-pass metabolism and increase the oral bioavailability of P-estradiol, estradiol-3-salicylate, and P-estradiol-3-anthranilate, ester prodrugs were synthesized and their oral bioavailabilities in dogs were evaluated... 

With these promoieties, the 3-phenolic hydroxy group of p-estradiol (the normally metabolized functional group) was blocked so that first-pass conjugative metabolism could be reduced. The relative bioavailability of estradiol was significantly improved when administered in these prodrug forms. A 17-fold increase was observed with the estradiol-3-salicylate. The P-estradiol-3-anthrani-late increased the systemic availability five-fold. 

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-... 

Alkoxyalkanoate esters have been used as prodrugs to improve the oral bioavailability of antiviral agents such as (+)-cyclaradine (carbocyclic arabino-furanosyl adenine) [41]. (+)-Cyclaradine has been shown to be effective against herpes simplex virus in tissue culture at noncytotoxic concentrations. Two prodrugs of (+)-cyclaradine, namely, (+)-cyclaradine-5 -methoxyacetate (CM) and (+)-cyclaradine-5,-ethoxypropionate (CE) (Fig. 2), may be promising candidates... 

Dopamine, a vasodilator, has been widely used for treatment of acute circulatory failure. However, since dopamine is rapidly metabolized when administered orally, its use has been limited to intravenous infusion. Murata et al., studied the bioavailability and the pharmacokinetics of orally administered dopamine (DA). The oral administration of DA to dogs resulted in an absolute bioavailability of approximately 3%. To minimize the extensive first-pass metabolism of DA, a dopamine prodrug, V-(/V-acetyl-l-mcLhionyl)-o,o-bis(cLhoxycarbonyl)dopamine (TA-870), was synthesized [28] (Fig. 6). Since DA is a substrate for both mono-... 

M Hussain, BI Aungst, F Shefter. Prodrugs for improved oral beta-estradiol bioavailability. Pharm Res 5(l) 44-47, 1988. 

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. 

F Harboe, C Larsen, MJ Johansen, HP Olesen. Macromolecular prodrugs. XV. Colon-targeted delivery—Bioavailability of naproxen from orally administered dextran-naproxen ester prodrugs varying in molecular size in the pig. Pharm Res 6(11) 919—923, 1989. 

K Murata, N Kazuo, K Kohano, MJ Sanejirna. Bioavailability and pharmacokinetics of an oral dopamine prodrug in dogs. J Pharm Sci 78(10) 812-814,... 

Steingrimsdottir, H.,etal. Bioavailability of aciclovir after oral administration of aciclovir and its prodrug valaciclovir to patients with leukopenia after chemotherapy. Antimicrob. Agents Chemother. 2000,... 

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