Review Article Drugs 29: 455-473 (1985) 0012-6667/85/0QO5-O455/$09.50/0 ® ADIS Press Limited All rights reserved. Prodrugs Do They Have Advantages in Clinical Practice? VJ. Stella, W.N A. Charman and V.H. Naringrekar Department of Pharmaceutical Chemistry, University of Kansas, Lawrence Summary Prodrugs are pharmacologically inactive chemical derivatives of a drug molecule that require a transformation within the body in order to release the active drug. They are designed to overcome pharmaceutical and/or pharmacokinetically based problems asso• ciated with the parent drug molecule that would otherwise limit the clinical usefulness of the drug. The scientific rationale, based on clinical pharmaceutical and chemical experience, for the design of various currently used prodrugs is presented in this review. The examples presented are by no means comprehensive, but are representative of the different ways in which the prodrug approach has been used to enhance the clinical efficacy of various drug molecules. The term 'prodrug' is used to describe com• bond will be designed to be cleaved efficiently by pounds which must undergo chemical transform• enzymatic or non-enzymatic means (Kupchan et ation within the body prior to exerting their al.? 1965), followed by the subsequent rapid elim• pharmacological or therapeutic action. The term ination of the released promoiety. 'prodrug' or 'proagenf was first used by Albert The term 'drug latentiation' has also been ap• (1958) who suggested that this approach could be plied to this concept. Harper (1959, 1962) de• used to alter the properties of drugs, in a temporary scribed drug latentiation as the chemical modifi• manner, to increase their usefulness, and/or to de• cation of a biologically active agent to form a new crease associated toxicity. compound which upon in vivo enzymatic attack will liberate the parent compound. The chemical alter• 7. The Prodrug Concept ation of the parent compound is such that the change in physicochemical properties will affect the The prodrug concept is illustrated in figure 1. A absorption, distribution and enzymatic metabol• drug whose usefulness is limited by adverse phys- ism. Such compounds have also been called bio- icochemical properties, such that it is not capable reversible derivatives and congeners, but 'prodrug' of overcoming a particular barrier, is chemically is now the most commonly accepted term (Higuchi modified via the attachment of a promoiety to gen• and Stella, 1975; Roche, 1977a; Sinkula and Yal- erate a new chemical entity, the prodrug, whose kowsky, 1975). properties are such that it is capable of traversing Clinically relevant prodrugs are abundant. Many the limiting barrier. Ideally, the promoiety/drug of the drugs that were developed as early as the Prodrugs in Clinical Practice 456 late nineteenth century are in fact prodrugs: for ex• terial, could not be used as a urinary tract antisep• ample, hexamine (methenamine) and aspirin are tic until it was formulated as an enteric-coated tab• prodrugs of formaldehyde and salicylic acid, re• let of hexamine. After absorption, hexamine is spectively. Aspirin is less corrosive than salicylic excreted in the urine, which if acidified, provides acid to the gastrointestinal mucosa and quantita• a medium in which formaldehyde is generated. tively releases salicylic acid in vivo by the action Here the problem overcome was one of transport of esterases. Formaldehyde, as a contact antibac• limitation, and site-specific delivery was achieved. Barrier to drug's usefulness Drug Non-toxic and rapidly excreted Fig. 1. Schematic representation of the 'prodrug' concept Prodrugs in Clinical Practice 457 2. Barriers to Drug Development as that phase involving the study of the absorption, distribution, metabolism and excretion of the drug. In figure 1, the term 'barrier' is used rather These studies provide valuable information about loosely. It is easy to envisage a true biological bar• the in vivo properties of a drug's limitations such rier, such as the blood-brain barrier, when dis• as poor absorption, too rapid elimination, and pre- cussing the problems of drug delivery to the central systemic metabolism. If these properties can be re• nervous system (CNS). However, there are various lated back to the physicochemical and dosage form other barriers that are not always recognised by end- properties of the system, then correction can be users of a drug product that must be resolved be• made. Occasionally, these corrections will require fore a new chemical entity can become a useful prodrug interventions. drug. Aliens and Simonis (1974) described the pro• The principal barriers identified in the phar• cess of drug development as occurring in three macokinetic phase are: phases: the pharmaceutical, pharmacokinetic, and 1. Incomplete absorption of the drug from the de• pharmacodynamic phases. The pharmacodynamic livery system or across biological barriers such phase, which involves the drug/receptor interac• as the gastrointestinal mucosal cells and the tion, is not a phase where prodrugs are usually con• blood-brain barrier sidered to act, although Bey (1978) has suggested 2. Too rapid or too slow transport of the drug to that suicide substrates or Kcat inhibitors (com• the body, i.e. the rate of drug action onset needs pounds containing latent reactive groupings which to be optimised are specifically unmasked by the action of target 3. Incomplete systemic delivery of an agent due to enzymes) can be considered as prodrugs. presystemic metabolism in the gastrointestinal lumen, mucosal cells, and liver 2.1 Pharmaceutical Phase 4. Toxicity problems associated with local irrita• tion or distribution into tissues other than the The pharmaceutical phase can be considered as desired target organ the phase of development which occurs between 5. Poor site specificity of the drug. the identification of a new chemical entity with There are numerous clinical examples and lit• measured or proposed therapeutic potential and its erature references on the use of prodrugs attempt• incorporation into a drug delivery system. The de• ing to solve the problems mentioned above. Many livery system may be one of the traditional forms of these examples have appeared in comprehensive such as tablets, capsules, injections, creams/oint• reviews (see table I). Some of the clinically or po• ments etc., or one of the new drug delivery modes, tentially clinically relevant examples, as well as e.g. transdermal delivery patches or implanted de• some of the problems associated with the use of vices. Two barriers in this phase to the develop• prodrugs, are presented in this article. The reviews ment of a commercially usable drug product are: listed in table I should be consulted for extensive 1. The aesthetic properties of the new molecule coverage of the subject. may limit its usefulness, e.g. odour, taste, pain upon injection, gastrointestinal irritability, etc. 3. Use of Prodrugs to Overcome 2. Formulation problems may become apparent, Pharmaceutical Barriers e.g. the drug is unstable, or because of its phys- icochemical properties, cannot be incorporated The formulation of a new chemical entity with into a particular type of dosage form. suspected therapeutic benefits requires that the drug be formulated into a delivery form that is chemi• 2.2 Pharmacokinetic Phase cally stable, free from taste and odour problems (particularly if it is for paediatric use or intended The pharmacokinetic phase can be considered for parenteral administration), and the drug/form- Prodrugs in Clinical Practice 458 Table I. Comprehensive review articles on prodrugs stance inhibiting its usage in paediatric formula• tions. Chloramphenicol palmitate, a sparingly so• Albert (1973) Selective toxicity luble ester of chloramphenicol, is practically Molecular pharmacology as a basis Ariens (1966) tasteless because of its low aqueous solubility for drug design (Glazko et al., 1952). Since the interaction of a drug Modulation of pharmacokinetics by Ariens (1971) or prodrug with taste receptors requires the drug molecular modulation to be sufficiently soluble in saliva, by lowering the Novel approaches in prodrug design Bodor (1982) aqueous solubility to mask a taste problem, one Novel bioreversible derivatives of Bundgaard (1982) runs the risk of creating a more serious problem, amides, imides, ureides, amines and i.e. incomplete dissolution of the prodrug in the other chemical entities not readily gastrointestinal tract, resulting in incomplete ab• derivatisable sorption. However, the commercially used form of Drug latentiation Digenis and cloramphenicol palmitate is efficiently hydrolysed Swintosky (1975); to active chloramphenicol by the action of pan• Harper (1959, 1962) creatic lipase on solid chloramphenicol palmitate Prodrugs as novel drug delivery Higuchi and Stella particles (Andersgaard et al., 1974). Interestingly, systems (1975) other polymorphs - different crystalline forms of Prodrug design Notari (1981) chloramphenicol palmitate - which are also taste• Design of biopharmaceutical Roche (1977a) less, do not provide good plasma concentrations of properties through prodrugs and chloramphenicol because of poor solubility and the analogues fact that the solid-to-solution transition is not ca• Rationale for design of biologically Sinkula and talysed by lipase. Other examples of the use of pro• reversible drug derivatives Yalkowsky (1975) drugs to mask taste are listed in table II. Prodrug approach in drug design Sinkula (1975) Odour is another aesthetic