Prodrugs improving absorption

A series of peptide prodrugs ofh-a-methyldopa were prepared and shown to exhibit high affinity for the peptide carrier system [32], In an in situ intestinal perfusion model, the prodrugs Phe-L-a-methyldopa (6.10) and l-a-methyldopa-Phe (6.11) showed permeabilities that were 10- and 20-times higher, respectively, than that of L-a-methyldopa. The other derivatives examined (Gly- and Pro-L-a-methyldopa, L-a-methyldopa-Pro) also had better permeabilities. These and other results indicate that the peptide transport system has a relatively low substrate specificity and can indeed be targeted by peptide prodrugs to improve absorption [33],... 

Fosamprenavir is a prodrug for amprenavi r, and al lows fewer capsules to be administered per day, due to improved absorption... 

Prodrugs can be used to increase or decrease the aqueous solubility, mask bitterness, increase lipophili-city, improve absorption, decrease local side effects, and alter membrane permeability of the parent molecule. For example, chloramphenicol has an aqueous solubility of 2.5mg/ml, but chloramphenicol sodium succinate, a prodrug, has an aqueous solubility of lOOmg/ml. Hydantoins also possess low aqueous solu-bilites that result in low and variable availability and precipitation following injection. In an effort to increase the aqueous solubility of phenytoin, Stella et prepared the ethyl and triethylamine esters... 

To minimize degradation and improve absorption of peptide and protein drugs administered orally, several factors are significant. First, peptide and protein drugs have to be protected from the acidic environment in the stomach and from enzyme degradation in the lumen and on the brush border of the small intestine. This may be accomplished by coadministration of peptidase inhibitors or by chemical modifications, such as analogs or prodrug approaches, or... 

Not all carboxylic esters arc easily hydrolyzed in vivo. Stcric inhibition around the ester in some cases prevents the prodrug from being hydrolyzed. This is. seen in the fi-lac-lams, in which it is often desirable to increase the hydropho-bicity of ihc agent to improve absorption or prevent distiolu-tion in the stomach where acid-catalyzed decomposition may occur. Simple esters or the carboxylic acid moiety, however, are not hydrolyzed in vivo to the active carboxylate (Scheme 5-8). 

Carfecillin (Fig. 10.39) is the prodrug for carbenicillin and shows an improved absorption through the gut wall. 

Adenine itself was successfully incorporated into a number of pharmaceuticals, Adefovir dipivoxil, also known as bis-POM PMEA, with trade names Preveon and Hepsera, is used for the treatment of hepatitis B and herpes simplex virus infection. It is an orally administered nucleotide analog as a reverse transcriptase inhibitor (NRTI). Reverse transcriptase is an enzyme crucial to viral production. A second NRXI that contains adenine is Tenofovir disoproxil fumarate (TDF), which has been used in the treatment of HIV/AIDS and hepatitis B. TDF is a prodrug of tenofovir (also known as PMPA) designed to improve absorption and cell permeability of the active moiety under the trade name Viread. Both adefovir dipivoxil and TDF are marketed by Gilead Sciences. 

D Fleisher, BH Stewart, GL Amidon. Design of prodrugs for improved GI absorption by intestinal enzyme targeting. Methods Enzymol 112 360-381, 1985. 

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. 

MR Harnden, RL Jarret, MR Boyed, D Sulton, RA Vene Hodge. Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxymethyl) but 1-yl] guanine (BRL 39123) with improved gastrointestinal absorption properties. J Med Chem 32 1738-1743, 1989. 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

Golomb, G., A peptide prodrug approach for improving bisphos-phonate oral absorption, J. Med. 

Prodrugs with improved oral absorption properties 287... 

PRODRUGS WITH IMPROVED ORAL ABSORPTION PROPERTIES... 

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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