Pharmaceutical research · 2007
Novel cyclic phosphate prodrug approach for cytochrome P450-activated drugs containing an alcohol functionality.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Huttunen Kristiina M, Mähönen Niina, Leppänen Jukka, Vepsäläinen Jouko, Juvonen Risto O, Raunio Hannu, Kumpulainen Hanna, Järvinen Tomi, Rautio Jarkko
Аннотация
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.
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.
Предметные рубрики MeSH
Aryl Hydrocarbon HydroxylasesBiotransformationBuffersCytochrome P-450 CYP2C19Cytochrome P-450 CYP3ACytochrome P-450 Enzyme SystemDrug DesignDrug StabilityHumansHydrogen-Ion ConcentrationHydroxylationIn Vitro TechniquesMicrosomes, LiverMixed Function OxygenasesOrganophosphatesOxidation-ReductionPhosphoric Monoester HydrolasesPolycyclic CompoundsProdrugsPropanolsRecombinant Proteins