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Design and Application of Prodrugs

During the past three decade it has become more obvious that the commonly used processes of delivering therapeutic agents to the sites of their action within the body are generally inefficient and unreliable. Optimization of the drug delivery and consequently improvement in drug efficacy implies an efficient and selective delivery and transport of a drug substance to its site of action. So attention has been focused on approaches, which aim at enhancing the efficacy and reducing the toxicity and unwanted effects of drugs controlling their absorption, blood levels, metabolism, distribution and cellular uptake. Prodrug design comprises an area of drug research, which is concerned with the optimization of drug delivery. A prodrug is pharmacologically inactive derivative of a parent molecule, which requires spontaneous, i.e. non-enzymatic, or enzymatic transformation within the body in order to release the active drug. A prodrug has improved delivery properties over the parent drug molecule. A molecule with optimal structural configuration and physico-chemical properties for eliciting the desired therapeutic response at its target site, does not necessarily posses the best molecular form and properties for its delivery to its site of ultimate action. Usually, only a minor fraction of doses administered reaches the target area and since most agents interact with non-target sites as well, an inefficient delivery may result in undesirable side effects. This fact of differences in transport and in situ effect characteristics for many drug molecules is the basic reason why bioreversible chemical derivatization of drugs, i.e. prodrug formation, is a means by which a substantial improvement in the overall efficacy of drugs can often be achieved. Prodrugs are designed to overcome pharmaceutically and/or pharmacokinetically based problems associated with the parent drug molecule, which otherwise would be of limited clinical use. The prodrug approach can be illustrated as shown in figure 1. Fig. 1. Schematic illustration of the prodrug concept. By attachment of a pro-moiety to the molecule or by otherwise modifying the compound, a prodrug is formed, which overcomes the barrier for the usefulness of the drug. Once past the barrier, the prodrug is ideally reverted quantitatively to the parent compound by a post-barrier enzymatic or non-enzymatic process. In the pharmacokinetic phase, i.e. the absorption, distribution, metabolism and excretion of the drug, major barriers, which may limit the usefulness of a drug, are: 1. Incomplete absorption of the drug across biological membranes such as the GI mucosa or the blood-brain barrier. 2. Incomplete systemic bioavailability of a drug due to presystemic metabolism (first-pass metabolism). 3. Too rapid absorption or excretion of the drug when a longer duration of action is desired. 4. Toxicity problems related to local irritation or distribution into tissues other than the desired target organ. 5. Poor site-specificity of the drug. The rational design of prodrugs can be divided into three basic steps: - identification of the drug delivery problem, - identification of the physico-chemical properties required for maximum efficacy or delivery, and - selection of a prodrug derivative which has the proper physico-chemical properties and which can be cleaved in the desired biological compartment. The oral route of drug administration is the most convenient, safest and most economical of the various routes, it has a number of disadvantageous: 1) destruction of some drugs by gastric acid or digestive enzymes ; b) precipitation or insolubility of some drugs in gastrointestinal fluids ; 3) formation of no absorbable complexes between drugs and food materials ; 4) variable rates of absorption resulting from physiological factors such as gastric emptying time, gastrointestinal motility and mixing ; and 5) irritation to the gastric mucosa with resultant nausea and vomiting. Poor bioavailability of an orally administered drug may be due to loo low lipophylicity, too low water-solubility, low acid-stability or extensive first-pass metabolism of the drug in intestine or liver. Several drugs are efficiently absorbed from the gastrointestinal tract, but show limited systemic bioavailability due to presystemic (or first-pass) metabolism or inactivation before reaching the systemic circulation.. This metabolism can occur in the intestinal lumen, at the brush border of the intestinal cells, in the mucosal cells lining the gastrointestinal tract or in the liver. First-pass metabolism can be avoided by other routes of administration such as sublingual, inhalation and partly by rectal route. However, the oral route is generally preferred. The prodrug approach has been successfully applied to a wide variety of drugs, e.g. ampicillin derivatives (pivampicillin, bacampicillin and talampicillin), ACE inhibitors (enalapril and pentopril), carbenicillin (carindacillin), N-acyloxymethyl derivative of allopurinol, inhibitors of the gastric H+/K+-ATPase (omeprasole), etc. Most of the applications have involved (a) enhancement of bioavailability and passage through various biological barriers, (b) increased duration of pharmacological effects, (c) increased site-specificity, (d) decreased toxicity and adverse reactions, (e) improvement of organoleptic properties and (f) improvement of stability and solubility properties. 1. Friis, G. J. and Bundgaard, H. (1996) Design and application of prodrugs. In A Textbook of Drug Design and Development, 2nd edited by P. Krogsgard-Larsen, T. Liljefors and U. Madsen, p.p. 351-385. Amsterdam: Harwood Academic Publishers, 2. Yalkowski, S.H. and Morozowich, W. (1980) A physical chemical basis for the design of orally active prodrugs. In Drug Design, Vo. IX, edited by E.J. Ariens, p.p. 121-185. New York: Academic Press.

Drug design; Prodrug; Prodrug design; Prodrug application

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