Effect of grapefruit juice on serum voriconazole concentrations in the mouse.
Voriconazole is a broad spectrum, triazole antifungal drug now well into the final phases of clinical trials in humans. During preclinical phases of development, it was found that when administered to mice, one of the more important animals used in the in vivo evaluation of antifungal compounds, serum voriconazole concentrations were very low at best and often undetectable. This was due to a combination of high clearance and extensive metabolism by cytochrome P450 enzymes. As a result, mice were abandoned as being suitable for further study of voriconazole and most subsequent work with voriconazole has been performed in the guinea pig. In this study, we show that the administration of grapefruit juice, a known inhibitor of cytochrome P450 enzymes, is effective in producing measurable serum concentrations of voriconazole in mice when the drug is administered once daily. Serum voriconazole concentrations were < 3 microg ml(-1) at all time points in mice not receiving grapefruit juice. In contrast, grapefruit juice administered by once daily gavage or continuously in lieu of water in the water bottle resulted in serum voriconazole concentrations ranging 0.4-2.6 and 1.8-5.8 microg ml(-1), respectively, with increasing concentrations observed over the 10-day evaluation period. Further studies to elucidate the precise mechanism of action and optimal dosing schedule in mice can now be performed to improve our understanding of the pharmacokinetics of voriconazole in the mouse.
Sugar
A M
AM
Evans Memorial Department of Clinical Research, Boston Medical Center, MA 02118, USA. asugar@medicine.bu.edu
Liu
X P
XP
D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D001628:Beverages; D002957:Citrus; D004334:Drug Administration Schedule; D018565:Food-Drug Interactions; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D065819:Voriconazole
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole