Phosphate Ester Prodrugs

Phosphate prodrugs offer several advantages for formulation and development of poorly water-soluble compounds. Phosphate prodrugs are chemically stable, their synthesis is usually straightforward in the presence of a hydroxyl moiety (Kearney and Stella, 1993), and the increases in solubility imparted by the dianionic phosphate group are often several orders of magnitude (Stella, 1996; Rodriguez et al., 1999; Zhu et al., 2000; Heimbach, 2003; Furfine et al., 2004). For oral dosage forms, the reduction or elimination of solubilizing excipients can lead to cost reduction through greater drug loading capacity (Sorbera et al., 2001; Becker and Thornton, 2004), providing a more convenient dosing regimen, especially for high dose compounds. Moreover, phosphate ester prodrugs are readily cleaved by endogenous phosphatases to rapidly release the pharmacologically active parent drug (McComb et al., 1979).

There are many examples of successful phosphate prodrugs for parenteral administration, including fosfluconazole (Bentley et al., 2002; Sobue et al., 2004), etoposide-phosphate (Greco and Hainsworth, 1996; Schacter, 1996), clindamycin-phosphate, (Soejima and Saito, 1994), hydrocortisone-phosphate (Arky, 2000), and fludarabine-phosphate (Grever et al., 1990; Rossi et al., 2004). Several phosphate prodrugs that have been at various stages in drug discovery or development include the antifungal SCH 59884 (Kim et al., 2002), PA2808 (Baker et al., 2004), ZD-6061 (Soltau and Drevs, 2004), camptothecin-phosphate (Hanson et al., 2003), and antitumor prodrugs of various combretastatins, including combretastatin-A4-phosphate, which is currently in Phase I/II clinical trials (Grosios et al., 1999; Hill et al., 2002; Pettit et al., 2002; NIH, 2004; Young and Chaplin, 2004). Aquavan® is a phosphate ester prodrug of the analgesic drug propofol (Banaszczyk et al., 2002) that employs a phosphonooxymethyl spacer approach that has been successfully employed for fosphenytoin and camptothecin (Stella, 1996; Hanson et al., 2003) to enhance enzymatic hydrolysis rates. Derivatization of tertiary amine-containing drugs such as loxapine resulted in quaternary amine phosphate prodrugs with greatly enhanced aqueous solubility (Krise et al., 1999a,b,c).

Very few phosphate prodrugs have been marketed exclusively for oral administration. Estramustine phosphate has been used since the mid 1970s for the management of prostate cancer (Nilsson and Jonsson, 1975; Perry and McTavish, 1995). Fosfosal, a phosphate prodrug of salicylic acid, has reduced gastrointestinal (GI) side effects compared to the parent compound (Ramis et al., 1988). Inorganic disodium monofluorophosphate (MFP) is on the market as an alternative to NaF for the oral treatment of osteoporosis. This unusual prodrug eliminates the gastric irritation by the reaction of gastric HCl with NaF (Rigalli et al., 1994; van Asten et al., 1996). In addition, the fluoride bioavailability of the fluoride-containing prodrug is nearly double that of NaF since precipitation of calcium fluoride is prevented. Pediapred® (Medeva Pharmaceuticals, Inc.) is a liquid formulation of prednisolone phosphate used to overcome the poor palata-bility of prednisolone tablets to children. Recently, fludarabine was marketed as an oral phosphate prodrug (Boogaerts et al., 2001) by Berlex-Schering. For fludarabine, marketing as the oral prodrug may have been a consequence of prior approval of its parenteral formulation, fludarabine-phosphate (Fludara®) and, thus, may not have been a deliberate phosphate prodrug strategy based on a biopharmaceutical advantage. Fosamprenavir, a novel oral phosphate prodrug of the antiviral drug amprenavir (Agenerase®) that allows a more simplified dosage regimen was recently approved in Europe and the US (Becker and Thornton, 2004); it is discussed later in this chapter as well as in another chapter in this book.

Why is it that very few phosphate prodrugs seem to survive beyond the discovery stage? One reason is that not all phosphate derivatives offer significant biopharmaceutical advantages compared to their parent drugs, and there are no clear guidelines to identify drug candidates for which this can be achieved. Criteria for suitable oral phosphate candidates were discussed by Fleisher (Fleisher et al., 1996). Oral phosphate prodrugs are especially promising for insoluble parent drugs that must be administered at high doses since, despite low solubility, "low-dose" compounds will be completely dissolved and absorbed within normal GI residence times. Thus, a phosphate prodrug strategy is most likely to succeed for drug candidates where absorption is dissolution-rate limited due to low solubility and high projected dose.

Dissolution rate limits to drug absorption can be evaluated by the familiar Noyes-Whitney equation (Eq. 1) (Noyes and Whitney 1897):

Equation 1.

This equation describes the dissolution rate for a solid solute into a non-reactive medium in units of mass/time. D is the diffusion coefficient of the drug or prodrug in the medium of dissolution, h is the diffusion layer thickness around the drug particles, S is the exposed surface area of the solid, Cs is the solubility of the drug, and Cb is the concentration of the drug in the bulk medium. S and Cs lend themselves to easy pharmaceutical manipulation to increase dissolution rates (Kearney, 1990).

Phosphate prodrugs markedly increase a drug's aqueous solubility, Cs, and consequently increase its dissolution rate (Amidon, 1981). Mass transport rates across the GI barriers are increased by soluble prodrugs due to their higher concentration gradients across the intestinal mucosa (Amidon, 1981; Fleisher et al., 1986, 1996; Stewart, 1986), as long as there are no offsetting decreases in partitioning into the membrane. Even when the latter is the case, absorption may still be increased if bioconversion maintains a higher parent drug concentration at the cell membrane-lumen interface. The maximum flux, or amount of parent drug passively absorbed per time per area can be expressed as Eq. 2 (Amidon et al., 1980):

Equation 2.

In this simplified equation, Jm is the mass flux in units of g/cm2s and Peff, the effective permeability coefficient, has the units of a velocity e.g., cm/s. Cb and Cs are as defined for Eq. 1 and are in units of g/cm3. Under sink conditions, when Cb = 0, the maximal flux is defined by Eq. 3 (Amidon et al., 1980,1985):

Equation 3.

Phosphate prodrug bioconversion at the intestinal brush border by membrane bound enzymes, such as alkaline phosphatase, is depicted in Figure 1 (Fleisher et al., 1985; Stewart, 1986). The concentration of the parent drug is elevated in the vicinity of the mucosal membrane due to enzymatic conversion of the prodrug, which can lead to local supersaturation of the parent drug (Heimbach et al., 2003a), resulting in a larger concentration driving force and absorptive flux. In

Figure 1. Absorption model with potential rate lmits for water-soluble phosphate prodrugs. Adapted from the literature (Stewart, 1986; Fleisher et al., 1996). The soluble (phosphate) prodrug provides a greater concentration driving force across the intestinal lumen. The cleavage of the phosphate group by membrane-bound alkaline phosphatases releases the usually lipophilic parent drug in the vicinity of the mucosal membrane. Potentially rate-limiting steps include: Dissolution/Solubility (not common); Enzymatic Bioconversion, i.e., enzyme-mediated parent drug generation; and Permeability/Transport of the parent drug. Enzyme-mediated supersaturation leading to precipitation of the parent drug after prodrug hydrolysis can negatively impact the prodrug strategy. Notably, in some cases, the prodrug can increase the solution concentration of the parent drug through supersaturation or solubilization from a prodrug surfactant effect (Heimbach et al., 2003a).

Figure 1. Absorption model with potential rate lmits for water-soluble phosphate prodrugs. Adapted from the literature (Stewart, 1986; Fleisher et al., 1996). The soluble (phosphate) prodrug provides a greater concentration driving force across the intestinal lumen. The cleavage of the phosphate group by membrane-bound alkaline phosphatases releases the usually lipophilic parent drug in the vicinity of the mucosal membrane. Potentially rate-limiting steps include: Dissolution/Solubility (not common); Enzymatic Bioconversion, i.e., enzyme-mediated parent drug generation; and Permeability/Transport of the parent drug. Enzyme-mediated supersaturation leading to precipitation of the parent drug after prodrug hydrolysis can negatively impact the prodrug strategy. Notably, in some cases, the prodrug can increase the solution concentration of the parent drug through supersaturation or solubilization from a prodrug surfactant effect (Heimbach et al., 2003a).

some cases the solubility of the parent drug is also enhanced in the presence of the surface-active phosphate prodrug (Heimbach et al., 2003a).

Many lipophilic drug substances are substrates of the multi-drug resistance 1 (MDR1) gene product P-glycoprotein (P-gp), which can limit systemic drug exposure after oral dosing (Lown et al., 1997; Ekins et al., 2002). Few, if any studies have been published in which a solubility-enhancing prodrug was demonstrated to saturate intestinal efflux or metabolism due to an increased solution concentration (Cs), leading to enhanced transepithelial flux and increased systemic exposure. A recent study described the use of a soluble dendrimer prodrug of propranolol to bypass efflux transporters and enhance oral bioavailability (D'Emanuele et al., 2004). However, propranolol is a highly permeable compound, where efflux is unlikely to be rate-limiting to absorption. For most drugs, efflux at the intestine is not clinically significant (Lin, 2003), except for a few low dose compounds generating intestinal drug concentrations that are too low to saturate the efflux pumps, i.e., at concentrations below the Michaelis constant (Km) (Lin, 2003).

However, the possibility that supersaturated drug solutions resulting from hydrolysis of soluble prodrugs in the vicinity of these pumps might saturate capacity-limited efflux should be considered as a strategy to increase intestinal absorption.

Was this article helpful?

0 0
Delicious Diabetic Recipes

Delicious Diabetic Recipes

This brilliant guide will teach you how to cook all those delicious recipes for people who have diabetes.

Get My Free Ebook


Responses

  • leevi
    How does a phosphate ester group increase solubility?
    7 months ago

Post a comment