PURPOSE: A cyclic phosphate prodrug of a descriptive molecule containing an alcohol functionality was designed, synthesized and characterized in vitro as a cytochrome P450 (CYP) -selective prodrug. MATERIALS AND METHODS: To achieve efficient CYP-oxidation and prodrug bioconversion, 1,3-cyclic propyl ester of phosphate was designed to have a C4-aryl substituent and synthesized using phosphorus(III) chemistry. The two-step bioconversion of the cyclic phosphate prodrug was evaluated in vitro using human liver microsomes and recombinant CYP enzymes. RESULTS: This cyclic phosphate prodrug underwent initial CYP-catalyzed oxidation and was mainly catalyzed by the CYP3A4 form. The hydroxylated product was slowly converted to a ring-opened intermediate, which subsequently transformed by beta-elimination reaction to a free phosphate. The free phosphate was further dephosphorylated by microsomal phosphatases, releasing the parent molecule with a free hydroxyl group. The cyclic phosphate was reasonably stable in buffer solutions at the pH range 1.0-9.0. CONCLUSIONS: Since CYP enzymes reside predominantly in the liver and secondarily in the small intestine, the results indicate that cyclic phosphate prodrugs represent a very feasible liver- or intestinal-targeted drug delivery strategy for drug molecules containing an alcohol functionality. This may potentially improve the efficacy and the safety profile of the alcoholic parent drugs.
PURPOSE: A cyclic phosphate prodrug of a descriptive molecule containing an alcohol functionality was designed, synthesized and characterized in vitro as a cytochrome P450 (CYP) -selective prodrug. MATERIALS AND METHODS: To achieve efficient CYP-oxidation and prodrug bioconversion, 1,3-cyclic propyl ester of phosphate was designed to have a C4-aryl substituent and synthesized using phosphorus(III) chemistry. The two-step bioconversion of the cyclic phosphate prodrug was evaluated in vitro using human liver microsomes and recombinant CYP enzymes. RESULTS: This cyclic phosphate prodrug underwent initial CYP-catalyzed oxidation and was mainly catalyzed by the CYP3A4 form. The hydroxylated product was slowly converted to a ring-opened intermediate, which subsequently transformed by beta-elimination reaction to a free phosphate. The free phosphate was further dephosphorylated by microsomal phosphatases, releasing the parent molecule with a free hydroxyl group. The cyclic phosphate was reasonably stable in buffer solutions at the pH range 1.0-9.0. CONCLUSIONS: Since CYP enzymes reside predominantly in the liver and secondarily in the small intestine, the results indicate that cyclic phosphate prodrugs represent a very feasible liver- or intestinal-targeted drug delivery strategy for drug molecules containing an alcohol functionality. This may potentially improve the efficacy and the safety profile of the alcoholic parent drugs.
Authors: P C Rensen; R L de Vrueh; J Kuiper; M K Bijsterbosch; E A Biessen; T J van Berkel Journal: Adv Drug Deliv Rev Date: 2001-04-25 Impact factor: 15.470