Concept of Prodrug

The prodrug concept has been used to improve undesirable properties of drugs since the late nineteenth century. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, these are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. Numerous prodrugs designed to overcome barriers to drug utilization have reached the market. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This chapter introduces the rationale behind use of the prodrug approach from past to present, and also considers the possible problems that can arise in future from inadequate activation of prodrugs.

Keywords

Prodrugs; drug latentiation; hard drugs; soft drugs; double prodrug

2.1 Concept of Prodrug

Many therapeutic drugs have undesirable properties that may become pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug application. Among the various approaches to minimize the undesirable drug properties, while retaining the desirable therapeutic activity, the chemical approach using drug derivatization offers perhaps the highest flexibility and has been demonstrated as an important means of improving drug efficacy (Han, 2000). The prodrug approach, a chemical approach using reversible derivatives, can be useful in the optimization of the clinical application of a drug. The prodrug approach gained attention as a technique for improving drug therapy in the early 1970s. Numerous prodrugs have been designed and developed since then to overcome pharmaceutical and pharmacokinetic barriers in clinical drug application, such as low oral drug absorption, lack of site specificity, chemical instability, toxicity, and poor patient acceptance (bad taste, odor, pain at injection site, etc.) (Stella, 1975). It is justified by the fact that once the barrier to the use of the parent compound has been overcome, these temporary forms can be converted to the free parent compound that can exert its pharmacological activity. The prodrug approach can be illustrated as shown in Figure 2.1.

2.2 Undesirable Properties Associated with Drug Molecules

There are many undesirable properties associated with drug molecules. These properties demonstrate restrictions in its use.

The poor drug delivery problem can be overcome by one of the following approaches:

Several barriers of nonpharmacokinetic and pharmacodynamic origin may prevent a drug from reaching the desired target. This includes pathological limitations, such as toxicity, high incidence of side effects, pharmaceutical limitations, psychological limitations, and also economic barriers. Most of these limitations can be overcome by the prodrug approach (Higuchi and Davis, 1970).

During the last two decades, there has been a steady improvement in the physicochemical, biopharmaceutical, and/or pharmacokinetic properties of pharmacologically active compounds by the implementation of a prodrug strategy.

The basic aim of prodrug design is to mask undesirable drug properties, such as low solubility in water or lipid membranes, low target selectivity, chemical instability, undesirable taste, irritation or pain after local administration, presystemic metabolism, and toxicity.

2.3 Prodrug Design: Past to Present

The first intentionally designed derivative of a drug molecule was introduced as long ago as 1899 by Schering, this was methenamine (or hexamine). Methenamine releases antibacterial formaldehyde along with ammonium ions in acidic urine and serves as a good example of a site-selective prodrug. At the same time, Bayer introduced aspirin (acetylsalicylic acid) as a less irritating form of the anti-inflammatory agent sodium salicylate. However, it remains unclear whether aspirin is a true prodrug or not. Although it was intended to work as a prodrug, aspirin inhibits irreversibly cyclooxygenase, the enzyme responsible for the formation of the key biological mediators, prostaglandins and thromboxanes. The parent drug, salicylic acid, is a weak reversible inhibitor of cyclooxygenase and thus cannot be considered a prodrug. However, aspirin is rapidly hydrolyzed in the intestinal wall and liver, as well as in the blood, to salicylic acid, which means that it acts, in fact, like a prodrug.

Later, Bayer introduced another prodrug, the antibiotic prontosil, in 1935. However, prontosil was not intentionally developed as a prodrug, because very soon it was found to release an active agent, para-aminophenylsulfonamide, by reductive enzymes. This led to the discovery of the widely used antibacterials, sulfonamides. Similarly, Roche discovered the prodrug activity of the antitubercular agent isoniazid more than 40 years after its introduction in 1952. Today, it is known that the bioactivation of isoniazid is catalyzed by the peroxidase enzyme and the generated reactive inhibits the biosynthesis of mycolic acid required for the mycobacterial cell wall.

Sometimes, unintentionally developed prodrugs can reveal a less appealing truth of the drug under the development. Heroin (diacetylmorphine), was marketed during the years 1898–1910 as a nonaddictive morphine substitute to suppress cough and cure morphine addictions. However, later it became known that, in fact, heroin is rapidly metabolized into morphine after oral administration.

There has been an explosive boost since the 1960s in the use of prodrugs in drug discovery and development. From the start of the twenty-first century, when property-based drug design became an essential part of drug discovery and development, it has been a time of real breakthroughs in prodrugs. Thus, day by day the number of prodrugs undergoing clinical trials is increasing and prodrug research is now becoming an integral part of drug design.

One interesting example of these blockbuster prodrugs is lisdexamfetamine dimesylate, the L-lysine prodrug of the psychomotor stimulant dextroamphetamine. It was designed to have less abuse potential than other amphetamines due to the slower release of the active parent drug if inhaled or injected. Another best-selling group of prodrugs is the proton pump inhibitors omeprazole and its analogs, which are site-selectively bioactivated to their active species in the acidic parietal cells of the stomach.

2.4 Definitions of Prodrug

The term “prodrug” or “proagent” was first introduced by Albert (1958) to signify pharmacologically inactive chemical derivatives that could be used to alter the physicochemical properties of drugs, in a temporary manner, to increase their usefulness and/or to decrease associated toxicity.

The concept given by Albert was later extended by Harper, who coined the term drug latentiation, which implies a time lag element or component. Later, the concept of prodrug and latentiated drugs for solving various problems was attempted and the definition of drug latentiation was extended to include nonenzymatic regeneration of parent compounds. Thus, such compounds have also been called “latentiated drugs,” “bioreversible derivatives,” and “congeners,” but “prodrug” is now the most commonly accepted term (Roche, 1977; Sinkula and Yalkowsky, 1975).

Usually, the use of the term implies a covalent link between a drug and a chemical moiety, though some authors also use it to characterize some forms of salts of the active drug molecule. Although there is no strict universal definition for a prodrug itself, and the definition may vary from author to author, generally prodrugs can be defined as pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules, enzymatically or non-enzymatically, to exert a therapeutic effect. Ideally, the prodrug should be converted to the original drug as soon as the goal is achieved, followed by the subsequent rapid elimination of the released derivatizing group (Stella et al., 1985; Banerjee and Amidon, 1985).

In simplified terms, prodrugs are masked forms of active drugs that are designed to be activated after an enzymatic or chemical reaction once they have been administered into the body. Prodrugs are considered to be inactive or at least significantly less active than the released drugs; therefore, salts of active agents and drugs, whose metabolites contribute to the overall pharmacological response, are not included in these definitions.

2.5 Rationale for the Use of...