The Prodrug Concept and New Drug Design and Development Thomas N. Riley Department of Pharmacal Sciences, Auburn University, Auburn, AL 36849 The discovery and development of new chemical entities (drugs) intended for the treatment of human disorders and diseases is a complex, prolonged, and expensive process (1, 2). Until recently, drug discovery has largely been an empirical process accompanied by a significant component of serendipitous observation. While not a particularly challenging process, empirical methods of drug discovery are responsible for many of the therapeutic agents currently available to humankind. The empirical approach primarily involves random biological screening of numerous chemical compounds obtained from either synthetic or natural sources. Compounds are then selected based upon favorable screening results and further developed from this point (termed lead compounds). The development of a significant knowledge base in the biomedical sciences has, in recent years, facilitated drug discovery based on a more rational approach to pharmacological intervention in pathophysiological processes. The potential therapeutic utility of rationally designed new chemical entities must also be rigorously established through pharmacological testing. Regardless of the approach taken to discovering new lead compounds i t is usually necessary to optimize their therapeutic potential as a part of the initial discovery and development process. The therapeutic utility of a new drug may he compromised by unfavorable physical andlor chemical properties. Further, the new drug may not favorably interact with the living system leading to reduced therapeutic activity. In addition, the side effects (adverse reactions) of the new drug may be of such frequency and severity as to preclude its therapeutic utility. There are a number of techniques that can be employed to optimize the therapeutic potential of a newly discovered chemical entity. Often, structural modification of the lead compound or synthesis of structurally related analogues, designed using established structure-activity relationships will lead to therapeutically useful new drugs. In some cases therapeutic optimization may require the development of a novel dosage form for the new drug so that i t may be administered by a similar or different route than originally employed. Prodrug design, earlier termed drug latentiation, is a commonly employed technique of new drug development that often results in an enhancement of the therapeutic utility of a drug (34). The most commonly accepted definition of a prodrug is that i t is a pharmacologically inert precursor to an active (parent) drug. Conversion of the prodrug to the parent drug occurs after administration by either chemical or enzymatic methods. Prior to formalization of the prodrug concept as a technique of new drug discovery and development in 1958, the term "drug latentiation" was used to describe this type of drug action (6,7). The prodrugs thatwere in use preceding recognition of the formal concept have been termed "accidental" or "empirical" prodrugs. Figure 1provides examples of accidental prodrugs such as chloral hydrate, a commonly used sedative agent, which is converted in vivo to its pbarmacologically active central nervous system (CNS) depressant, trichloroethanol. Similarly, methenamine, a frequently used urinary tract antiseptic, is a prodrug of the active anti-
Figure 1. Examples of "accidental" prodrugs
bacterial substance, formaldehyde. Formaldehyde is chemically released from methenamine in the normally acidic bioenvironment of the kidneys. The design of a prodrug usually involves derivatization of the parent drug itself. The prodrug concept of drug design is illustrated in Figure 2. The structures of most prodrugs are bipartate in nature consisting of a pharmacologically inactive promoiety covalently linked to the parent drug structure. The comnlexitv of a rod run structure mav ranee from a simple este; derGative-of anacidic p a r e n t d r u g t o the inclusion of structural features of the oromoietv- reauirine . sophisticated chemical or hiochemical~echanismsto gene; ate the parent drug species. In the design of a therapeutically useful prodrug it is important that the prodrug form itself lack significant pharmacological activity and that, upon biotransformation, it he converted to the active parent drug and a pharmacologically inactive promoiety. Further, it is essential that the covalent bond between promoiety and parent drug be of balanced stability to permit pharmaceutical formulation of the nrodrue while. at the same time. nermittine cleavage at the appropriate ti& and site. The covalent link': age must he suitably labile to undergo either chemical or enzymatic cleavage a t the desired site and/or time in the bioenvironment. The relative lability of the covalent bonding between promoiety and parent drug can he modified in the design of a a rod rug so that bioactivatiou of the orodrua. occurs at specific site& the body. Other prodrug types include tripartate prodrugs in which and pirent drug are linked together by a special a typeofconnecror group [promoiety-link-parent drug] (8). Trinartate orodrues mav be of value when oroblems excessive stagility o i t h e Eovalent link in hipartate prodrugs reduces their abilitv to liberate the active drue in vivo. Mutual prodrugs invoke the coupling of two acti;e drug structures so that each acts as the prodrug of the other (9). Mutual prodrugs may he of particular therapeutic utility when the pharmacological actions of the product parent drugs are compatible, i.e., synergistic or additive in action. Polymeric prodrugs are formed by bonding a parent drug to a polymer. This technique of prodrug design is often utilized to provide timed release of the parent drug in vivo. Volume 65 Number 11 November 1988
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As cited previously, one of the primary uses of prodrugs is to optimize the therapeutic utility of a new lead compound. The prodrug concept has also been employed in an attempt to improGe the safety and/or efficacy of existing drugs. Often this technique proves to be more economically feasible than the development of a new chemical entity to replace the existing drug. Therapeutic deficiencies of new or existing drugs usually result from problems encountered in the three phases of drug action, pharmaceutic, biopbarmaceutic, and pharmacodynamic (10). Figure 3 illustrates these phases of drug action. The pharmaceutic phase refers to the chemical and physical environment of the drug prior to its absorption into the living system and includes the dosage form of the drug as well as tissues encountered at the site of administration. The biopharmaceutic phase of drug action includes absorption, distribution, hiotransformatiou, and elimination of the drug. The pharmacodynamic phase deals with the bioenvironment of the drug a t its pharmacological site(s) of action. Problems associated with any of these three phases of drug action can result in either a subtherapeutic or toxic response of the patient to drug therapy.
Figwe 2. The pmdrug concept.
Prodrug Utlllty and the ~harrnaceutlcPhase A necessary step in drug therapy is to incorporate the parent drug into a suitable dosage form (formulation) that is convenient for administration of the drug to the patient and that will facilitate the absorption of the drug
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Figure 3. The phases of drug action.
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into the patient's circulatory system (central compartment). Often the intrinsic chemical and/or physical properties of a drug present problems of stability, compatibility, and/or solubility in a particular formulation. The drug may have poor taste or odor characteristics t h a t could lead to poor patient acceptance of the product. Prodrug development from a parent drug t h a t experiences
Figwe 4. Prodrug Improvement of &emical and physlcal properties. Flgure 0. Prodrug improvement of ampiclllln stability.
Flgure 5. Prodryl improvemem of chemical stability.
Figure 7 . Steroid hamane prdrugs of varying solubility.
problems with respect to its incorporation into an appropriate dosage form canoften ohviateanumber of these difficulties.
lions of the drug that are useful for administering epinephrine ras its prodrua~to the eve for the treatment of certain onhthalmicdisord& Concentrated aqueous solutions of ampicillin, a widely used penicillin antibiotic, lack stability due to the tendency of the antibiotic to undergo autoaminolysis, i.e., intermolecular nucleophilic reaction between the alpha-NH2group on the side chain of one molecule with the beta-lactam function (four-membered r i n d of a second molecule. Autoaminolvsis results in a loss of antibiotic activity. Hetacillin, a prodrug of ampicillin formed bv condensine acetone with the uarent penicillin, is much more stahle inconcentrated aqueius solutions since the nucleophilic aloha-NH? function is masked (Fig. 6).
Prodrugs and Parent Drug Stability In manv cases orohlems of drue instabilitv in a dosaee form can be overcome by physical modificatiod of the dosage form itself. For example, many of the penicillin antibiotics are unstable in aqueous solution and are marketed in a dry powder form for reconstitution with water a t the time the drug is dispensed by the pharmacist. In cases when physical modification cannot achieve drug stability i t is necessary to chemically modify the parent drug via prodrug derivatization. For examole. durine the develoument of the broad-swectrum antihiitid cefam&dole sodikn it was found that iyiitalline forms of the drua were difficult to uurifv and lacked long-term stahility. ~tu%iesrevealed t h a t the &ate (format# ester prodrug of cefamandole sodium was highly crystalline, easier to purify, and stable on relatively longterm storage (Fig. 4). The naftate ester function of cefamandole cleaves quite readily in slightly alkaline solution as well as in hlood, therehy releasing the active antibiotic even as the oroduct is beine" reconstituted with water for treatment of serious bacterial infections by injection. E~ineobrine has been used in medicine for manv vears. . . The therapeutic utility of this hormone has been h&dered hv the relative ease of oxidation of the catechol function within its structure. Conversion of epinephrine to its borate prodrug (Fig. 5) facilitates the formulation of aqueous solu-
Nonproprie(ary (generic) names of drugs are officiallyassigned the U S . Adopted Names (USAN) program. Cenain consactsons have men adopted for common radicals and adducrs found in druqs, 8.g.. naflate for formate. by
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Prodrugs and Formulation Compatibility Water is the preferred solvent for preparation of liquid dosage forms of drugs such as oral liquids and injections; however, in many cases, the solubility of the active drug in water is too low to allow preparation of an aqueous formulation. Converselv a dosaee form of the drue in a lioid solvent may be desired. ~ h e s e d o s a g eforms provide exiended release of the drug from intramuscular (IM) or topical sites of administration, therehy facilitating less frequent dosing of the patient. In this case, low lipid soluhilitv of the drue mav in not permit formulation of anapproprinre~concentrat~on an oil solvent. The prodrug concept is often employed to alter the soluhilitv characteristics of a narent drug ~~-~ for - ~ for--- mulation purposes. For example, most of the natural steroid hormones and their svnthetic derivatives have undesirable solubility characteristics in regard to preparation of aqueous or lipid dosaee forms. Steroid hormones lend themselves quite nicely to the design of hioreversible derivatives (prod ' ~ @ )since most contain alcoholic hydroxyl Eroups that can readily be esterified with either a water-soluhiliring or lipidsolubilizing moiety (Fig. 7 ) . Hydrocortisone is widely used in the treatment of a wide variety of disorders. ~reparatiouof
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)\ 4J NHWCHCI. J--po/x
Figure 8. Prodrug desolubiliration for purposes of taste improvement.
an aqueous parenteral dosage form of hydrocortisone requires esterification of the steroid with a polyprotic acid such as succinic acid or phosphoric acid in order to convert the neutral steroid to an acidic derivative. The acidic derivative can then be neutralized with an appropriate alkali for conversion to a water.soluhle salt formsewhg as a prodrug of hydrocortisone as a result of rapid hydrolysis by tissue enzymes, e.g., esterases. On the other hand, a prodrug of hydrocortisone of enhanced lipid solubility can he formed by esterificationof the hormone with a suitablecarboxylic acid. The resulting prodrug can then he dissolved in an appropriate lipid solvent, administered directly into skeletal muscle tissue (1M) and provide a prolonged supply of hydrocortisone bv slow release from the oil followed bv. hvdrolvtic . . activation. Prodrugs and Improvement of Patient Acceptance of Drug Therapy Ohviouslv oatients must take their medications in order to benefit fro& the intended therapeutic effects. If the drug has an unnleasant taste. a bad odor or ~ r o d u c e sirritation a t the site of administration, patients are less likely to comply with their ohvsician's instructions for administerine the medication. ~ r o d r u have ~ s found utility in masking
