| Summary: | 碩士 === 國立成功大學 === 臨床藥學研究所 === 94 === Introduction. Since food and drugs are taken together frequently, it is important to investigate the food-drug interactions. Recent studies revealed that grapefruit juice inhibited the catalytic activity of CYP3A and resulted in an increase in the oral bioavailability of the drugs that are metabolized by CYP3A. Other fruit juice-drug interactions have also been documented, for example the interaction of cranberries with the CYP2C9 substrate warfarin. Cranberry is popular in markets in Taiwan, and it has been used in for a wide variety of therapeutic purposes, including the reduction of the recurrence of urinary tract infection.
Purpose. In this study, the effect of cranberry juice on the metabolism of tadalafil, an oral selective phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction and a CYP3A substrate, was investigated to explore the inhibitory effect of cranberry juice on CYP3A activity.
Methods. The concentrations of tadalafil and its metabolites in biological matrices were measured by reverse-phase HPLC methods using gradient or isocratic elution mode. The inhibitory effect of cranberry juice on the in vitro CYP3A-mediated metabolism of tadalafil was investigated using rat liver microsomes. The in vivo pharmacokinetic interaction of cranberry juice with tadalafil was examined in rats.
Results. Cranberry juice displayed non-competitive type of inhibition on in vitro CYP3A activity. The extent of inhibition depended on the amount of juice added, and it increased as the pre-incubation time increased, indicating that cranberry juice contains a mechanism-based inhibitor. In comparison with water, the area under the concentration-time curve（AUC）of tadalafil was approximately 1.6-fold higher when cranberry juice（2ml）was taken orally 30 min before the oral administration of tadalafil（10mg/kg）in rats. In contrast, the elimination half-life and AUC of tadalafil administered intravenously were not altered by the administration of cranberry juice.
Conclusions. Cranberry juice demonstrates significant inhibition of rat CYP3A activity in vitro. Furthermore, cranberry juice impairs the function of enteric but not hepatic metabolism of tadalafil in rats, thereby enhancing the systemic exposure of tadalafil.
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