The Solubility of Prodrugs
An effective prodrug needs to be soluble so that it can reach the target site and affect the desirable pharmacologic effects. Prodrugs are designed to circumvent drug limitations such as poor solubility in the aqueous and lipid phases. Therefore, most prodrugs are soluble in the body compartment where they are expected to affect their pharmacologic actions. The solubility of prodrugs can be altered by the addition of certain functional groups. For example, prodrug esters are designed to augment their lipophilic properties so that water-soluble drugs can easily traverse the cell membranes (Zawilska, Wojcieszak and Olejniczak 2). Their solubility in the aqueous phases is also improved by using phosphate esters and amides. In some cases, hydrophilic hydroxyl groups contain pharmacologically active substances. Acylation with aliphatic or aromatic carboxylic acids is carried out to improve their solubility in the lipid phase. To improve the water solubility of prodrugs, the hydroxyl groups of the parent drug are usually esterified with carboxylic acid products with other functional groups, for instance, amino or hydroxyl groups. These groups confer hydrophilicity or increased aqueous solubility to the prodrug molecules.
A novel approach to improving the solubility of prodrugs has been demonstrated in the hydrogenation of naproxen (an analgesic) to produce a hydrogelator, which improves its solubility and eliminates the need for a carrier molecule (Majumder et al. 10254).
The Absorption of Prodrugs
The efficacy of prodrugs is determined by their ability to be absorbed through oral and non-oral routes. The rapid absorption of the drug into the target cells is often necessary for a faster pharmacotherapeutic action of a drug (Okudaira et al. 580). Therefore, the absorption of most prodrugs is modified to match the anticipated action of the active drug. The advancement of oral bioavailability of drugs is among the most notable innovations since the discovery of prodrugs, which is attributed to improving their oral absorption (Zawilska, Wojcieszak and Olejniczak 3). Cancer treatment has also recorded immense progress by improving the absorption of anticancer agents. For example, Capecitabine (5′-deoxy-5-fluorocytidine carbamate), which is a tripartite prodrug undergoes fast and extensive oral absorption following oral administration. Liver carboxylesterases then act on the drug to yield 5′-deoxy-5-fluorocytidine that is further deaminated in the liver and cancerous cells by cytidine deaminase (Zawilska, Wojcieszak and Olejniczak 8). Ultimately, thymidine phosphorylase converts the metabolite to an extremely cytotoxic 5’-fluorouracil within the tumors.
Biostability of Prodrugs
The active drug is liberated from its dormant form before, in the course of, or following the absorption of the prodrug. Certain drugs can only be freed after they have arrived at the targets of their actions (Zawilska, Wojcieszak, and Olejniczak 2). Additionally, a prodrug needs to amplify the bioavailability and therapeutic value of a parent drug. Therefore, the preferred biostability of a prodrug varies with the site of release of the active drug. For prodrugs that are liberated after reaching their target sites, they should remain stable to ensure maximum absorption into the target sites. The biostability of prodrugs also aims at reducing presystemic metabolism, to enhance time rundown, elevating organ or tissue-selective supply of the active compound.
The biostability of prodrugs is influenced by the ease with which enzymes act on the prodrug to liberate the active compound. For example, the esterification of prodrugs with phosphate groups increases their biostability because endogenous phosphatases act rapidly on phosphate prodrugs. The functional groups present on the prodrug also determine the biostability of the drug. For example, drugs that require stability in the aqueous phase are formulated as phosphate prodrugs because amino acid ester exhibit inferior aqueous stability while amide prodrugs undergo partial in vivo bioconversion (Huttunen, Raunio, and Rautio 755).
References
Huttunen, Kristiina M., Hannu Raunio, and Jarkko Rautio. “Prodrugs—from Serendipity to Rational Design.” Pharmacological Reviews 63.3(2011):750–771. Print.
Majumder, Joydeb Mahua Rani Das, Jolly Deb, Siddhartha Sankar Jana, and Parthasarathi Dastidar. “β‑Amino Acid and Amino-Alcohol Conjugation of a Nonsteroidal Anti-Inflammatory Drug (NSAID) Imparts Hydrogelation Displaying Remarkable Biostability, Biocompatibility, and Anti-Inflammatory Properties.” Langmuir 29.32(2013): 10254−10263. Print.
Okudaira, Noriko, Tomoko Tatebayashi, Graham C. Speirs, Izumi Komiya, and Yuichi Sugiyama. “A Study of the Intestinal Absorption of an Ester-Type Prodrug, ME3229, in Rats: Active Efflux Transport as a Cause of Poor Bioavailability of the Active Drug.” The Journal of Pharmacology and Experimental Therapeutics 294.2(2000):580-587. Print.
Zawilska, Jolanta B., Jakub Wojcieszak, and Agnieszka B. Olejniczak. “Prodrugs: A Challenge for the Drug Development.” Pharmacological Reports 65.1(2013):1–14. Print.