Prodrugs concepts

Peptide-Prodmgs and the Cyclic Peptide-Prodrug Concept I 535... 

Since the introduction of the prodrug concept during the late 1950s, many such compounds which increase the oral bioavailability of small pharmacophores have... 

K. D. Bagshawe, Antibody Directed Enzymes Revive Anti-Cancer Prodrugs Concept , Br. J. Cancer 1987, 56, 531-532 K. D. Bagshawe, Antibody-Directed Enzyme/Pro-drug Therapy (ADEPT) , Biochem. Soc. Trans. 1990, 18, 750-752. 

Serious medication errors, including some leading to death, have resulted from the interpretation of the Cerebyx product labeling. The terminology on the label, which previously indicated the concentration as being 50 mg of phenytoin equivalents (PE) per milliliter, was misinterpreted as the total number of PEs per vial. Furthermore, health professionals were reportedly confused by the expression phenytoin equivalents, a prodrug concept introduced for this product. As a result, massive fosphenytoin overdoses were mistakenly administered. 

Figure 2. Prodrug conception of azomethine prodrugs of (i )-a-methylhistamine...

Several pharmacological studies were earned out to substantiate the proposed prodrug concept for (/< )-a-methylhistamine (12). The parent compound of this series of azomethines is the 2-hydroxybenzophenone derivative of (ft)-a-methylhistamine which is designated BP 2.94 (36). To evaluate the desired protection against HMT metabolization, BP 2.94 (36) was tested as a possible substrate in the presence of S-adenosylmethionine in comparison to histamine and ( )-a-methylhistamine (12). As a result no methylation of the prodrug 36 was observed, whereas both primary amines displayed similar Km- and Fmax-values [6],... 

The ratio of CNS and plasma values of liberated (R)-a-methylhistamine (12) underlines the suitability of these azomethines to realize the above-mentioned prodrug concept (Figure 3). In conclusion, the pharmacokinetic properties of the prodrugs can be shifted to the desired direction by varying the substitution pattern of the pro-moiety. 

Bagshawe, K. D. Antibody directed enzymes revive anticancer prodrugs concept. Br. J. Cancer 56 531-532, 1987. 

Figure 16.1 A diagrammatic representation of the prodrug concept where a pharmaceutically active drug is converted to an inactive compound to overcome pharmaceutical and biological barriers between the site of administration and the site of action...

Scheme 64 The prodrug concept applied to drug with a carboxylic function.

The concept, also called distal hydrolysis or the double prodrug concept, is illustrated by the use of 2-acyloxymethylbenzoic acids as amine protective functions, providing amides with the lability of esters (Figure 36.18a) and by the use of substituted vinyl esters [= (2-oxo-l,3-dioxol-yl)methyl esters] as lipophilic cascade carriers for carboxylic acid-containing drugs such as ampicillin or a-methyldopa or various cephalosporins (Figure 36.18b). 

The present review deals essentially with enhancement of gastrointestinal availability cf drugs through prodrug administration, but some other aspects of the prodrug concept are also discussed briefly. 

Another area of considerable interest is the use of the prodrug concept for better kinetic properties of angiotensin-converting enzyme inhibitors (Sections.2) or fibrinolyticenzymes (70). 

Bagshawe K. Antibody directed enzymes revive anti-cancer prodrugs concept. British... 

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