Ester prodrug

Kre merov4 M, H0I5 A, Pohl R, Masojidkovi M, Andrei G, Naesens L, Neyts J, Balzarini J, De Clercq E, Snoeck R (2007b) Ester prodrugs of cychc l-(S)-[3-hyioxy-2-(phosphonomethoxy)propyl]-5-azacytosine synthesis and antiviral activity. J Med Chem 50 5765-5772... 

Fosphenytoin Fosphenytoin is a water-soluble, phospho-ester prodrug of phenytoin that is rapidly converted to phenytoin in the body. It is compatible with most IV solutions and is well tolerated as an IM injection, even with the large volumes associated with loading doses (20 to 30 mL).19 It is dosed in phenytoin equivalents (PE), and it can be infused three times as fast as phenytoin, up to 150 mg PE/minute. The loading dose for patients not taking phenytoin is 15 to 20 mg PE/kg. It can be an advantage to use IM fosphenytoin when IV access cannot be obtained immediately and in patients with poor venous access. Although it has fewer cardiovascular side... 

V-Ethyl carbamate esters of fenoldopam, used for treatment of acute circulatory failure, provide another example of a carbamate ester prodrug. The intrinsically short half-life and extensive first-pass metabolism of fenoldopam limit its oral administration. /V-Ethyl carbamate esters of fenoldopam provide elevated plasma fenoldopam levels and increases in the renal blood flow of significantly greater duration than when the parent compound is administered orally [30],... 

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... 

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-... 

T Anders, LA Svensson. Bambuterol, a carbamate ester prodrug of terbutaline, as inhibitor of cholinesterases in human blood. Drug Metabol Dispos 16(5) 759-763,... 

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. 

SA Varia, VJ Stella. Phenytoin prodrugs VI In vivo evaluation of a phosphate ester prodrug of phenytoin after parenteral administration to rats. J Pharm Sci 73(8) 1087-1090, 1984. 

DS Chien, H Sasaki, H Bundgaard, A Buur, VHL Lee. (1991). Role of enzymatic lability in the corneal and conjunctival penetration of timolol ester prodrugs in the pigmented rabbit. Pharm Res 8 728-733. 

Naesens, L., Clercq, E. de, Van den Mooter, G., Kinget, R., Augustijns, P., Inhibition of intestinal metabolism of the antiviral ester prodrug bis(POC)-PMPA by nature-identical fruit extracts as a strategy to enhance its oral absorption an in vitro study, Pharm. Res. 1999, 16, 1035-1040. 

Han, H.-K., D.-M. Oh, and G. L. Amidon. Cellular uptake mechanism of amino acid ester prodrugs in Caco-2/hPEPTl cells overexpressing a human peptide transporter. Pharm. 

J. H., In vitro and in vivo evaluation of intestinal barriers for the zwitter-ions L-767,679 and its carboxyl ester prodrug L-775,318, Drug Metab. Disp. 1998, 26, 520-527. 

Drugs may also undergo hydrolysis by intestinal esterases (hydrolases), more specifically carboxylesterases (EC 3.1.1.1) in the intestinal lumen and at the brush border membrane [58, 59]. It has been shown that intestinal hydrolase activity in humans was closer to that of the rat than the dog or Caco-2 cells [60]. In these studies, six propranolol ester prodrugs and p-nitrophenylacetate were used as substrates, and the hydrolase activity found was ranked in the order human > rat Caco-2 cells > dog for intestinal microsomes. The rank order in hydrolase activity for the intestinal cytosolic fraction was rat > Caco-2 cells = human > dog. The hydrolase activity towards p-nitrophenylacetate and tenofovir disoproxil has also been reported in various intestinal segments from rats, pigs and humans. The enzyme activity in intestinal homogenates was found to be both site-specific (duodenum > jejunum > ileum > colon) and species-dependent (rat > man > Pig)-... 

Aciclovir is used extensively in prophylaxis and treatment of infections caused by herpesviruses. The L-valyl ester prodrug of aciclovir, valaciclovir, has been developed during the past decade and enhances the 20% oral bioavailability of aciclovir... 

There are few drugs that are thioesters, but you may recall that one of the intermediates in the oxidation of aldehydes by aldehyde dehydrogenase is a thioester involving the thiol of the enzyme (Fig. 30 in Chapter 4), which is readily hydrolyzed back to the native form of the enzyme, a thiol, and the carboxylic acid product. Some drugs that are carboxylic acids, such as enaloprilate, are administered as ester prodrugs (enalopril), which are more readily absorbed from the intestine than the carboxylic acid and are then readily hydrolyzed to the active drug by esterases as mentioned in Chapter 1 (Fig. 1 in Chapter 1). 

Fig. 41 The monoclonal, 6D9, raised against phosphonate [124] catalysed the hydrolysis of one possible regio-isomer [125] of a phenacetyl ester prodrug derived...

Hansen LB, Christrup LL, Bundgaard H (1992) Enhanced delivery of ketobemi-done through porcine buccal mucosa in vitro via more lipophilic ester prodrugs. Int J Pharm 88 237-242... 

In addition to peptide-based studies, degradation and absorption kinetics of a homologous series of acyclovir ester prodrugs have been studied using the in situ perfusion model [25, 26], The studies showed that due to high esterase activity of the rat nasal mucosa (96% disappearance of hexanoate prodrug of acyclovir in 960 min), the rat in situ model is an acceptable model to screen the nasal absorption of prodrugs. 

Yang C, Gao H, Mitra AK (2001) Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir. J Pharm Sci. 90 617-624. 

Annaert P, Kinget R, Naesens L, de Clercq E, Augustijns P (1997) Transport, uptake, and metabolism of the bis(pivaloyloxymethyl)-ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine in an in vitro cell culture system of the intestinal mucosa (Caco-2). Pharm Res 14 492-496. 

Annaert P, Tukker JJ, Van Gelder J, Naesens L, de Clercq E, Van den Mooter G, Kinget R, Augustijns P (2000) In vitro, ex vivo, and in situ intestinal absorption characteristics of the antiviral ester prodrug adefovir dipivoxil. J Pharm Sci 89 1054-1062. 

Tak RV, Pal D, Gao H, Dey S, Mitra AK. Transport of acyclovir ester prodrugs through rabbit cornea and SIRC-rabbit corneal epithelial cell fine. J Pharm Sci 90 1505-1515 (2001). 

He X, Sugawara M, Kobayashi M, Takekuma Y, Miyazaki K (2003) An in vitro system for prediction of oral absorption of relatively water-soluble drugs and ester prodrugs. Int J Pharm 263 35 14... 

X. Song, P. L. Lorenzi, C. P. Landowski, B. S. Vig, J. M. Hilfinger, and G. L. Amidon. Amino acid ester prodrugs of the anticancer agent gemcitabine synthesis, bioconversion, metabolic bioevasion, and hPEPTl-mediated transport. Mol Pharm 2 157-167 (2005). 

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