Stability of valacyclovir: implications for its oral bioavailability.
The absolute bioavailability of the prodrug valacyclovir, the l-valyl ester of acyclovir, after oral administration is approximately 54.5%. Since premature hydrolysis of this prodrug in the intestinal lumen may be a possible reason for its incomplete bioavailability and the chemical and enzymatic stability of the valacyclovir has been investigated. Release rates were investigated in both phosphate buffers with varying pH as well as in human and dog gastrointestinal fluids. The stability of the prodrug was found to be dependent on pH. This prodrug is chemically stable along the acidic pH side (under 4), while the prodrug degrades in alkaline medium through a base-catalyzed pseudo-first-order kinetics. The degradation of the prodrug valacyclovir progressed faster in intestinal fluid than in phosphate buffer at the same pH. There was no appreciable release of valacyclovir neither in the human and dog stomach contents nor in phosphate buffers at pHs fewer than 4, although its degradation was fastest in the human and dog stomach contents. In light of this result, we can conclude that the degradation of the valacyclovir in the upper intestinal lumen is probably one of the causes of its poor bioavailability.
Granero
Gladys E
GE
Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, 5000 Córdoba, Argentina. glagra@mail.fcq.unc.edu.ar
Amidon
Gordon L
GL
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry*; D001682:Biological Availability; D002021:Buffers; D004285:Dogs; D005750:Gastric Juice / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D007422:Intestines / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry
D000998:Antiviral Agents; D002021:Buffers; D011355:Prodrugs; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir