Prodrug Strategy in Drug Development Kelemen Hajnal1, Hancu Gabriel1*, Rusu Aura1, Varga Erzsébet2, Székely Szentmiklósi Blanka1
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Acta Medica Marisiensis 2016;62(3):356-362 DOI: 10.1515/amma-2016-0032 UPDATE Prodrug Strategy in Drug Development Kelemen Hajnal1, Hancu Gabriel1*, Rusu Aura1, Varga Erzsébet2, Székely Szentmiklósi Blanka1 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy, Tîrgu Mureş, Romania; 2 Department of Pharmacognosy and Phytotherapy, Faculty of Pharmacy, University of Medicine and Pharmacy, Tîrgu Mureş, Romania Prodrugs are chemically modified derivatives introduced in therapy due to their advantageous physico-chemical properties (greater stability, improved solubility, increased permeability), used in inactive form. Biological effect is exerted by the active derivatives formed in organism through chemical transformation (biotransformation). Currently, 10% of pharmaceutical products are used as prodrugs, nearly half of them being converted to active form by hydrolysis, mainly by ester hydrolysis. The use of prodrugs aims to improve the bioavailability of compounds in order to resolve some unfavorable characteristics and to reduce first-pass metabolism. Other objectives are to increase drug absorption, to extend duration of action or to achieve a better tissue/organ selective transport in case of non-oral drug delivery forms. Prodrugs can be characterized by chemical structure, activation mechanism or through the presence of certain functional groups suitable for their preparation. Currently we distinguish in therapy traditional prodrugs prepared by chemical derivatisation, bioprecursors and targeted delivery systems. The present article is a review regarding the introduction and applications of prodrug design in various areas of drug development. Keywords: prodrugs, classification of prodrugs, drug development, optimization of bioavailability Received: 01 October 2015 / Accepted: 04 July 2016 Introduction In essence a prodrug is an inactive, bioreversible deriva- One of the effective methods of modern research in the tive of an active drug which undergoes enzymatic and/or field of medicine is the development of prodrugs that have chemical transformation in vivo in order to release the ac- gained increasingly more importance in current therapy. tive parent drug, which can then exhibit its desired phar- A prodrug refers to a pharmacologically inactive com- macological effect [16,17]. pound which is transformed into an active substance by These ideas led to the development of a relatively large either chemical or metabolic processes. Nowadays approxi- number of prodrugs; the type of prodrugs depending on mately 10% of drugs used in therapy are administered as the specific properties of the drug that requires improve- prodrugs, and about half of these are hydrolyzed to the ment and the type of functionality that is present in the active form, in particular by hydrolysis of esters (figure 1) active drug [11]. [1-10]. Prodrugs are inactive derivatives of active substances The actuality of prodrugs in modern therapy is demon- with optimized physico-chemical properties (higher sta- strated by the fact that in the last ten years several books bility, improved solubility or increased permeability), that in this field have been published and thousands of articles suffer a biotransformation in the body whereby are exert- in scientific databases are investigating new potential mol- ing their pharmacological action [18]. ecules [11-13]. Prodrugs can be defined also to be medicines which have specific protective groups, in order to prevent unwanted Prodrug concept properties of the parent molecule. In most cases, prodrugs The prodrug concept has been used to improve undesirable are simple chemical derivatives that are only one or two properties of drugs since the late 19th century, but it was chemical or enzymatic steps away from the active parent only at the end of the 1950s that the actual term “prod- drug. However, some prodrugs lack an obvious carrier or rug” was introduced for the first time by Adrien Albert for promoiety but instead result from a molecular modifica- drugs that are inactive by themselves but which form an tion of the prodrug itself, which generates a new active active derivative by biotransformation. The concept was compound [19]. completed by Harper in 1959 which introduced the term The place and speed of biotransformation are closely re- of drug latentiation referring to drugs that were specifically lated to chemical structure, as well as the pharmacokinetic designed to require bioactivation [14]. properties of the molecule. This definition is the most appropriate even at present The concept of prodrug has to be differentiated from time and is consistent with the IUPAC definition which drugs that are active of their own, but by biotransforma- states that: a prodrug is a compound that undergoes biotrans- tion are forming one or more active metabolites and the formation before exhibiting pharmacological effects [15]. biological effect occurs as a common result of the original drug and metabolites. These drugs are “limited” prodrugs * Correspondence to: Gabriel Hancu (e.g. diazepam, carbamazepin) [11]. E-mail: [email protected] Kelemen Hajnal et al. / Acta Medica Marisiensis 2016;62(3):356-362 357 Fig. 1. The chemical structure of a few frequently used prodrugs In some cases, a prodrug may consist of two pharma- • increasing absorption from the gastrointestinal tract cologically active drugs that are coupled together in a after oral administration, single molecule, so that each drug acts as a promoiety for • obtaining parenteral preparations, the other. Such derivatives are called “codrugs” (e.g. sul- • masking unpleasant tastes, odors, tamicillin, sulfasalazine, benorilate, levodopa-entacapone) • avoiding injection site irritation or pain, [11,20,21]. • preventing rapid administration site inactivation, Recently the concept “hard-drug” and “soft-drug” were • increasing passage through the blood-brain barrier, introduced. “Hard-drugs” are designed to contain struc- • tissue/organ specific drug administration, tural characteristics necessary for the desired pharmacolog- • decrease in multidrug resistance, ical activity in a form that is not susceptible for chemical • side effects - and toxicity profile improved. or metabolic transformation, in order to avoid the produc- Prodrugs can be more effective, safer and more conveni- tion of toxic derivatives or to increase pharmacological ent in administration than conventional forms [26,27]. efficiency. “Soft drug” are active substance with planned metabolism which after exercising its effect is metabo- Classification of prodrugs lized into inactive and harmless metabolites and is rapidly Prodrugs can be classified taking in consideration their cleared from the body; thus “soft-drugs” can be considered chemical structure, mechanism of activation and the mod- to be opposite to prodrugs. ified functional groups [2,28]. The purpose of soft drugs’ development is to achieve a 1. By chemical criteria can be distinguished: therapeutic effect locally, eliminating systemic effects and • conventional prodrugs - obtained by chemical de- adverse reactions (e.g. remifentanil, esmolol) [22-24]. rivatization; the desired objective is to optimize trans- port properties; they are also called “carrier-linked The purpose of designing prodrugs prodrugs” as on the parent molecule are grafted func- 1. Improving bioavailability when the drug candidate is not tional groups that promote absorption. drug-like due to unfavorable physical properties as: • bio precursors – those substances which were not de- • poor water solubility, signed by conscious planning, but their activation in • low lipophilicity, the body occurs through chemical reactions. Such • chemical instability, prodrug is lovastatin, some vitamins (e.g. B1, B6), • unacceptable taste or smell, which after phosphorylation or oxidation (e.g. vita- • local irritation, pain. min D) are exercising their physiological role [11,29]. 2. Improving bioavailability when the drug candidate is not • drug delivery systems: drug-like, due to pharmacokinetic properties: – drug - polymer conjugates, where the drug is bin- • low bioavailability, ding to a macromolecule that favors its transport • poor penetration through biological membranes, – drug - antibody conjugates, target delivery is per- • increased first-pass metabolism, formed by antibody. • slow absorption by parenteral route, 2. By activation mechanism can be distinguished: • rapid absorption/elimination instead of long-lasting • drugs which suffer enzymatic activation – can be effect, planned; problems may occur due to biological vari- • lack of specificity in certain tissues [23-26]. ability between species, genetic polymorphism, drug The specific objective of prodrug design is to optimize interaction potential. unfavorable physicochemical properties, to increase chemical • drugs which suffer non-enzymatic activation – it is and/or metabolic stability, to achieve planned delivery. spontaneous, however inadequate chemical stability Prodrugs with optimized pharmacokinetic properties can create problems in conservation before use. have the following advantages: Classification by activation mechanism is based on the 358 Kelemen Hajnal et al. / Acta Medica Marisiensis 2016;62(3):356-362 types of reactions that result the active form, as: ing bioavailability. In drug development there are some • hydrolysis (ester, amide, imide, ether etc.); important physicochemical properties as appropriate solu- • oxidation; bility, adequate lipophilicity, good