Lipidic Prodrugs for Drug Delivery: Opportunities and Challenges


Prodrugs present inactive drug precursors intended to undergo enzymatic/chemical transformation in the body, thus liberating the active parent drug (Stella 2004). The strategy of designing a prodrug is used to improve physicochemical features of the drug moiety, and by doing so overcome absorption, distribution, metabolism, excretion and toxicity (ADMET) barriers. In addition, overcoming physicochemical deficiencies leads to improved site specificity, enhanced pharmacological effect, better formulation possibilities and facilitated drug administration (Testa 2009). In the process of prodrug development, various changes to polarizability, lipophilicity, H-bonds, steric factors, solubility, permeability, chemical/enzymatic stability and affinity toward enzyme/transporter can be introduced in order to overcome numerous barriers (Rautio et al. 2018).

The prodrug approach has evolved from being used as a salvage option to being purposely designed at very early stages in the drug development (Huttunen et al. 2011). If this strategy is reflected on already in the preclinical phases of the drug development, the prodrug strategy may expedite and facilitate the entire clinical development (save resources and time) and, eventually, commercialization of a drug product. Ten percent of all marketed drugs can be categorized as prodrugs (Rautio et al. 2018). Often, the prodrug approach is quicker and more efficient than formulation approaches, making it a more appropriate option than returning to the drawing board in pursuit of a completely new drug.

Traditionally, the prodrug approach aims to alter different physicochemical and biopharmaceutical features of the parent drug; covalent binding of the drug to the hydrophilic or lipophilic functional groups increases drugs’ solubility and permeability (Stella 2010). This approach may improve intestinal absorption following oral administration, alter certain metabolic pathways, allow skin penetration, blood-brain barrier (BBB) permeation, and improve safety profile (Dahan et al. 2014). The modern prodrug approach aims to target specific transporters or enzymes, providing site-specific drug release (Gupta et al. 2013; Sun et al. 2010). This approach accounts for molecular/cellular factors (i.e., membrane transporters influx/ efflux, cellular proteins expression/distribution), allowing improved systemic bioavailability following oral administration, organ or tissue selective drug activation, and drug targeting to a specific site (Dahan et al. 2012; Han and Amidon 2000). Tissue and cell targeting using prodrugs that are carefully designed for this purpose is a new and promising direction within the prodrug approach (Ettmayer et al. 2004).

The Challenges of Oral Drug Absorption

Oral route of drug administration is the most frequent and suitable route of drug administration. This chapter will largely focus on orally delivered prodrugs, and ways to overcome barriers that compromise bioavailability following oral administration. Absorption encompasses the processes of drug transit through gastrointestinal lumen to the intestinal membrane and drug movement to the blood. Following ingestion and prior to permeation, the drug needs to be dissolved and appear close to the intestinal membrane in its molecular form. This step presents the key obstacle for absorption of lipophilic drugs with low aqueous solubility. The solubilization of drugs in these cases can be achieved with biliary and/or pancreatic surfactants, such as bile acids, phospholipids (PL), cholesterol, which can make mixed micelles responsible for the drugs’ solubilization, and enabling the drug to reach the enterocyte membrane.

Solubilized drug is now presented for the following stage in the absorption cascade, the permeation through the luminal membrane of the intestine, through the mechanism of passive diffusion or through active transport (via transporters on the apical side of enterocytes). This may present a rate-limiting stage for hydrophilic drugs with low lipid solubility. In addition, the unstirred water layer (UWL) in line with the intestinal membrane presents the barrier for hydrophobic drug moieties.

If the drugs overcome these barriers, they can now move into the enterocytes. At this stage, the drug can be influenced by the metabolic activity of enzymes and/or efflux transporters which returns it into the intestinal lumen. Metabolic activity of Cytochrome P450 (CYP) enzymes influences a considerable number of drugs; in the intestines, CYP450 3A4 is responsible for 70%-80% of drug metabolism (Wacher et al. 1998). P-glycoprotein (P-gp) is a multiple drug resistance (MDR) efflux transporter that mediates the transfer of drugs from the enterocyte to the lumen of intestine, hence decreasing the amount of absorbed drug (Giacomini et al. 2010). Localization and substrate selectivity of CYP3A4 and P-gp is largely similar, and there is a notable interplay between the two barriers in terms of drug absorption (Benet 2009).

Furthermore, the drug exits the enterocyte, enters the lamina propia, and gets absorbed into the portal circulation; a number of highly lipophilic drugs, and lipidic prodrugs circumvent the portal circulation by undergoing lymphatic transport, which will be discussed in Section 5.2.1 (Porter and Charman 2001). Within portal blood flow, the drug molecule is subjected to first-pass hepatic metabolism, which is a major obstacle that limits drug bioavailability, especially in cases of highly lipophilic molecules (e.g., some hormones) that are absorbed completely from the intestinal lumen, but undergo extensive hepatic metabolism, resulting in extremely low amount of the free drug in systemic circulation (low oral bioavailability) (Horst et al. 1976).

Prodrug Types

Good understanding of physicochemical and biological parameters (i.e., low solubility and/or permeability, efflux transporters responsible for drug elimination, high extent of hepatic metabolism, biliary excretion) that present an obstacle for optimal drug bioavailability is necessary in order to design the optimal prodrug candidate. High throughput screening techniques and combinatorial chemistry strategies have led to the development of highly lipophilic drug molecules. Biopharmaceutical Classification System (BCS) categorizes all drugs into four categories based on the solubility and permeability; lipophilic drugs are classified as class 2, due to their low solubility and high intestinal permeability, where low aqueous solubility in the intestinal tissue presents a major obstacle for drug bioavailability (Amidon et al. 1995). On the contrary, in case of drugs that belong to BCS class 3, which are classified according to their high solubility and low permeability, intestinal permeability presents a key barrier for bioavailability. Highly challenging drugs with both low solubility and permeability belong to class 4 of the BCS. Providing adequate bioavailability for drugs that belong to BCS class 2, 3, or 4 is oftentimes difficult; however, the prodrug approach can aid in turning a challenging drug into a promising candidate.

Two main approaches are employed in the prodrug approach: designing a hydrophilic prodrug, whose lipophilicity is lower than that of the parent drug, and lipophilic prodrug, with lipophilicity higher than that of the parent drug. Creating a hydrophilic prodrug is usually based on connecting the drug to the specific functional groups (such as phosphate, hemisuccinates, aminoacyl esters, that ionize at the physiological pH), where the enhanced solubility in comparison to the parent drug results in improved absorption (Ettmayer et al. 2004). However, it should be noted that the drug liberation from the prodrug needs to occur post-absorption, and not in the lumen of intestine, which is a challenging task due to the need to balance hydrophilicity and lipophilicity required for solubilization and permeation through the intestinal wall, respectively (Amidon et al. 1980).

The focus of this chapter is lipidic prodrugs, including the main lipid physiological pathways, opportunities that lipid prodrugs offer, as well as challenging aspects of this approach. Lipid prodrugs are formed by covalent conjugation between the parent drug and the lipid carrier, resulting in a prodrug that has higher lipophilicity in comparison to the parent drug (Lambert 2000). The lipid moiety can be a fatty acid (FA), triglyceride (TG), phospholipid (PL) or steroid. Due to the lipophilic nature of the carriers, lipidic prodrugs can have extremely low solubility, and in this case a prodrug design needs to reflect a well-balanced approach between suitable lipophilicity on one hand and using the assets of such approach on the other (Markovic et al. 2018).

Prodrugs should be designed in a way that they are stable prior to reaching absorption site; it is a significant challenge to keep both chemical stability and biological (i.e., enzymatic) activation. Cautiously designed lipidic prodrug can exploit endogenous lipid processing pathways and overcome the transport of the prodrug molecule across absorption barriers. Among other advantages of this approach are possibility of tissue/organ-specific targeting, increased permeation through biological barriers (e.g., intestinal wall, BBB), improving drug delivery difficulties, overcoming limitations in terms of drug loading to delivery systems, and decreased toxicity.

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