Prodrugs slow release

A number of prodrugs in clinical use are esters of fatty acids. For example, haloperidol decanoate is of interest in slow-release preparations. This compound was hydrolyzed by such hydrolases as purified carboxylesterase but was reported to be stable in human blood or plasma and in a variety of rat tissue homogenates [107], The source of this apparent lack of reactivity was competitive binding to blood and tissue proteins. In other words, protein binding sequesters this very lipophilic prodrug and prevents enzymatic hydrolysis, thereby slowing its activation and prolonging its in vivo effects. 

The hydrolysis of esters is usually rapid whilst that of amides if often much slower. This makes esters suitable as prodrugs (see Section 9.8) and amides a potential source for slow release drugs. 

Prodrugs can be used to give a slow release of drugs which would be too toxic to give directly. Propiolaldehyde is useful in the aversion therapy of alcohol, but is not used itself since it is an irritant. However, the prodrug pargylene can be converted to propiolaldehyde by enzymes in the liver (Fig. 8.19). 

Anabolic steroids such as nandrolone and testosterone, anti-inflammatory glucocorticoids such as methylprednisolone, and contraceptives such as estradiol and levonorgestrel all have slow-release formulations of their ester prodrugs in the market. 

Because the mechanism of action of sulfasalazine is not related to the sulfapyridine component, and since sulfapyridine is believed to be responsible for many of the adverse reactions to sulfasalazine, mesalamine alone can be used. Mesalamine can be used topically as an enema for the treatment of proctitis, or given orally in slow-release formulations that deliver mesalamine to the small intestine and colon (Table 34—5 and Fig. 34-1). Slow-release oral formulations of mesalamine such as Pentasa release mesalamine from the duodenum to the ileum, with about 75% of the drug passing into the colon. Olsalazine is a dimer of two 5-aminosalicylate molecules linked by an azo bond. Mesalamine is released in the colon after colonic bacteria cleave olsalazine. Balsalazide is a mesalamine prodrug that is enzymatically cleaved in the colon to produce mesalamine. The recommended daily doses of the oral mesalamine derivatives are intended to approximate the molar equivalent of mesalamine present in 4 g of sulfasalazine. At present, snlfasalazine is nsed in preference to oral mesalamine derivatives, mainly becanse it costs mnch less. However, it is not tolerated as well as the mesalamine altematives. Becanse the oral mesalamine formulations are coated tablets or grannies, they should not be crushed or chewed. 

In order to maximize the exposure and thus the viral spectrum of 12 in the clinic, the highly water soluble Tris salt (aqueous solubility >10 mg/mL) of prodrug 13 was selected for advancement. To reduce the relatively high peak to trough ratio observed after oral dosing with this class of molecules, a slow release formulation was developed and was shown to facilitate absorption from the entire GI tract [69],... 

These esters (p-trifluoromethyl- and p-fluoro-benzoate) are prodrugs of DOXO [52] and have been used in cellular uptake studies. Despite the low cytotoxicity with respect to the parent anthracyclines, these esters may find apphcation for slow release. In fact, this possibility has already been explored. Some 14-(co, CO, -trifluoromethyl)-alkyl-anthracycline derivatives 57 (Fig. 7) with satisfactory carcinostatic properties have also been patented [53]. 

The hydrophobic tail of the ester is deliberately designed to enable a slow release of the prodrug into the bloodstream, where the prodrug is rapidly hydrolyzed to produce the active drug. 

Several prodrugs of Hourouracil were obtained by acylation or carbamoylation of N-1 and/or N-3 atoms of the pyrimidine ring of 1. In particniar, an oral drug Carmofur (2) which is 1-hexylcarbamoyl derivative of 1 was launched in Japan in 1981 and later - in other countries [35], The carbamate moiety in 2 decomposes gradually in neutral water or in basic conditions, but it is strongly resistant to acidic hydrolysis and hence can survive acid in the stomach. The 1-hexylcarbamoyl moiety also facilitates the rapid uptake of 2 through the cell membrane [36]. The metabolic activation of Carmofur involves oxidation and scission of the side-chain with slow release of 1 [37]. Two main routes of the side chain transformation are (o-oxidation and ((o-l)-oxidation metabolites 40-43 were detected after adnunis-tration of Carmofur (Fig. 3) [38]. Non-enzymatic hydrolytic decomposition of 2 and its metabolites also contributes to release of 1. 

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