Entacapone Phosphate

Entacapone phosphate is an investigational phosphate ester prodrug of entacapone (Figure 5), a drug marketed in 1999 as ComtanĀ® by Novartis and Orion Pharma for the treatment of Parkinson's disease (PD) which results from low levels of dopamine in the brain. Common treatment of PD involves oral administration of levodopa, a precursor of dopamine that can cross the blood-brain barrier, combined with an inhibitor of dopa decarboxylase (DDC), such as carbidopa, to inhibit decarboxylation of levodopa in the periphery. Entacapone is clinically used as an adjunct to the levodopa/carbidopa (SinemetĀ®) therapy (Chong and Mersfelder, 2000; Forsberg et al., 2002). It acts peripherally as a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), the main enzyme responsible for metabolic loss of levodopa after blockage of DDC (Chong and Mersfelder, 2000; Henchcliffe and Waters, 2002).

Entacapone Phosphate

Entacapone

Figure 5. Structures of the investigational prodrug entacapone phosphate and its precursor, entacapone.

Entacapone Phosphate

Entacapone

Figure 5. Structures of the investigational prodrug entacapone phosphate and its precursor, entacapone.

Entacapone exhibits linear pharmacokinetics over the dose range of 5 mg to 800 mg. While it is absorbed rapidly, within 1 h of administration, its oral bioavailability (~25-35%) is low (Heikkinen et al., 2001). The factors contributing to this poor bioavailability have not been resolved. Savolainen et al. (2000b) suggested that it may be caused by entacapone's low aqueous solubility and slow dissolution in the pH range of the stomach and upper small intestine. To improve the aqueous solubility and dissolution rate of entacapone, Leppanen and coworkers (Leppanen et al., 2000a,b; Heimbach et al., 2003b) have synthesized a prodrug by splicing a phosphate functional group onto entacapone using phosphorus oxychloride as a phosphorylation agent. The resulting prodrug had an aqueous solubility of over 30 mg/mL at pH 7.4 while that of entacapone was 1.75 mg/mL at the same pH value. The prodrug was enzymatically labile, yet highly stable toward chemical hydrolysis (Leppanen et al., 2000b). This phosphate prodrug strategy did not succeed, as the prodrug did not yield higher entacapone plasma levels in rats (Heimbach et al., 2003b), which may be the result of entacapone's low intestinal permeability. Other attempts to increase entacapone's bioavailability included the synthesis of lipophilic prodrugs (Savolainen et al., 2000a) to enhance its permeability.

The main barrier to achieving high bioavailability for entacapone, however, may lie in its high systemic clearance (Heikkinen et al., 2001), which may not be saturated by optimizing presystemic drug absorption through a prodrug approach. In general, metabolic liability is unlikely to be addressed via a solubility-enhancing prodrug strategy, and ideal parent drugs are those with low-to-medium clearance.

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