Prodrug Design and Development for Improved Bioavailability across Biological Barriers

The prodrug concept has been used to alter and mask the undesirable properties of the active parent drug. Prodrugs are pharmacologically inactive compounds which are converted into its active product by metabolic transformation like enzymatic and chemical transformations. The rationale behind the development of prodrugs is the delivery of appropriate concentrations of drug to the target cells as compared to administration of parent drug. There are many pharmacokinetic, pharmaceutical and pharmacodynamic barriers encountered by the drug. Prodrug approach has been found to be very helpful to overcome these barriers to a certain extent. This article describes and takes a review on the concept of a prodrug, barriers overcome by prodrug approach, various prodrug designs significant for distribution of drugs which are transporters proteins and bioactive enzymes, different types of transporters i.e SLC transporters & ABC transporters and Enzyme-targeted prodrug therapy. Further, this article focuses on the main chemical moieties and some of the examples of parent drugs using these moieties will be discussed. Dr. M.S Rathore * , Sandeep Kumar Maharishi Markandeshwar College of Pharmacy, M.M University, Mullana (Ambala), Haryana, India. Submission: 3 September 2016 Accepted: 7 September 2016 Published: 25 September 2016 www.ijppr. humanjournals.com Citation: Dr. M.S Rathore et al. Ijppr.Human, 2016; Vol. 7 (2): 187-220. 188 INTRODUCTION A prodrug is pharmacologically inactive compound that is converted into its active drug by a metabolic biotransformation. Prodrugs enhanced the usefulness of various therapeutic agents by altering their physicochemical properties, pharmacokinetics, and biopharmaceutical properties. Prodrug might alter the tissue distribution, efficacy, and toxicity of parent drug. Below are some reasons why prodrug approach should be used in drug design: ∙ Improved aqueous solubility. ∙ Improved absorption and distribution ∙ Site specificity ∙ Improved stability of drugs ∙ For prolonged release ∙ To reduce toxicity ∙ In poor patient acceptability ∙ In formulation problems. It has been reported that about 10% of drugs marketed all over the world can be classified as prodrugs. [1] In 1867, Cahn and Hepp introduced acetanilide as a prodrug for the first time in medical practice. Acetanilide undergoes hydroxylation in the body and gets converted to biologically active compound acetaminophen having both antipyretic and analgesic activities. The main ideology of using prodrug approach is to mask undesirable properties of the parent compound like low solubility in water, irritation or pain after local administration, low target selectivity, chemical stability and enzymatic stability etc. [2, 3] In general prodrug is introduced to optimize absorption, distribution, metabolism, excretion and toxicity of the parent drug. This review aims to discuss and present the information about the prodrug concept in details, the role of transporters in drug absorption and the different chemical moieties that can be used to design prodrug for improvement of aqueous solubility. Research being conducted in past 10 years in this area is taken into account and attempt has been made to present available information in a lucid manner in this review. www.ijppr. humanjournals.com Citation: Dr. M.S Rathore et al. Ijppr.Human, 2016; Vol. 7 (2): 187-220. 189 Concept of Prodrug The fundamental principle of the prodrug is to eradicate undesirable properties of drug-like low aqueous solubility, low lipid solubility, poor target selectivity, undesirable taste, low chemical stability, presystemic metabolism and to mask irritation upon local administration etc. [4] The term prodrug was first introduced by Adrein Albert in 1958, according to Adrein Albert prodrug is biologically inactive derivative of parent drug which undergoes chemical and enzymatic conversions in the body to release biologically active parent drug. The simple illustration of prodrug concept is given in figure 1. Fig. 1: A simple Illustration of Prodrug Concept Extracellular Space Intracellular Space E n zy m at ic /C h em ic al B io tr an sf o rm at io n www.ijppr. humanjournals.com Citation: Dr. M.S Rathore et al. Ijppr.Human, 2016; Vol. 7 (2): 187-220. 190 Classification of Prodrugs based on structure of the drug The prodrugs are classified into various categories as follows: (A) Carrier-linked Prodrugs (B) Bioprecursors (C) Macromolecular Prodrugs (D) Spacer or Linker Prodrugs (A) Carrier-Linked Prodrugs: A carrier-linked prodrug is a complex that comprises an active drug which is temporarily attached to some carrier with covalent linkage. The carrier group can be detached enzymatically. After administration to the body, the prodrug undergoes biotransformations and converted to the active compound. [5] The ideal carrier should have following properties: ∙ It should save the drug until it reaches the site of therapeutic action. ∙ Confine the drug at the site of therapeutic action. ∙ Allow the liberation of the drug by chemical or enzymatic action. ∙ It should bear biochemical inertness. ∙ To be easily prepared and inexpensively. ∙ It should be inert and stable. Carrier-linked prodrugs are further classified as: (i) Bipartite Prodrugs (ii) Tripartite Prodrugs (iii) Mutual Prodrugs (i) Bipartite Prodrug: A bipartite prodrug is a prodrug comprised of one carrier linked to the parent drug. The examples of bipartite prodrugs are Prednisolone sodium phosphate (1), latanoprost (2). (Figure 2) www.ijppr. humanjournals.com Citation: Dr. M.S Rathore et al. Ijppr.Human, 2016; Vol. 7 (2): 187-220. 191 O P O O-