TY - JOUR
T1 - Plasma pharmacokinetics and tissue penetration of a novel antifungal triazole, bay r 3783, and its long-lasting active metabolite, bay u 3625, in rabbits
AU - Lee, James W.
AU - Ritter, Wolfgang
AU - Lecciones, Julius
AU - Kelly, Patrick
AU - Pizzo, Phillip A.
AU - Walsh, Thomas J.
N1 - Funding Information:
We express our gratitude to Joanne Peter, Vanessa Thomas, and Robert Schaufele for their technical assistance and to the staff of the Office of Laboratory Animal Science of the National Cancer Institute for their excellent animal care. This study was supported in part by a grant from Cutter Biological (Berkeley, CA, USA).
Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 1991/6
Y1 - 1991/6
N2 - The plasma pharmacokinetics and tissue penetration of Bay R 3783 (BR), a new antifungal triazole, and one of its active metabolites, Bay U 3625 (BU), were studied in rabbits. Plasma levels of BR and BU were determined simultaneously in five rabbits for six days after a single oral dose of 20 or 40 mg/kg BR. For BR, the mean Cmax was 1.9±0.4 mg/l, the Tmax2.0±0.7 h,the AUC∞ 7.5±1.6 mg . h/l, and the terminal plasma T1/2 2.1±0.1 h. For BU, the mean Cmax was 0.84±0.09 mg/l, the Tmax 24±4 h, the AUC∞ 61.9±6.5 mg h/l, and the plasma T1/2 was 48±3 h. In a multi-dose study, the plasma BR clearance during wash-out gradually diminished, suggesting possible metabolite inhibition of BRs biotransformation. No hepatic or renal toxicity was seen after 28 days of dosing with BR 40 mg/kg/d. Both BR and BU penetrated well into tissues, with tissue drug concentrations over three times higher than in plasma at multiple tissue sites. Persistence of BU in plasma, however, resulted in prolonged, higher tissue levels of BU than of BR. We conclude that BR is converted to a long-lasting active metabolite BU, that persistence of BU in tissue is prolonged, and that these properties may permit BU to contribute significantly to the antifungal activity of BR.
AB - The plasma pharmacokinetics and tissue penetration of Bay R 3783 (BR), a new antifungal triazole, and one of its active metabolites, Bay U 3625 (BU), were studied in rabbits. Plasma levels of BR and BU were determined simultaneously in five rabbits for six days after a single oral dose of 20 or 40 mg/kg BR. For BR, the mean Cmax was 1.9±0.4 mg/l, the Tmax2.0±0.7 h,the AUC∞ 7.5±1.6 mg . h/l, and the terminal plasma T1/2 2.1±0.1 h. For BU, the mean Cmax was 0.84±0.09 mg/l, the Tmax 24±4 h, the AUC∞ 61.9±6.5 mg h/l, and the plasma T1/2 was 48±3 h. In a multi-dose study, the plasma BR clearance during wash-out gradually diminished, suggesting possible metabolite inhibition of BRs biotransformation. No hepatic or renal toxicity was seen after 28 days of dosing with BR 40 mg/kg/d. Both BR and BU penetrated well into tissues, with tissue drug concentrations over three times higher than in plasma at multiple tissue sites. Persistence of BU in plasma, however, resulted in prolonged, higher tissue levels of BU than of BR. We conclude that BR is converted to a long-lasting active metabolite BU, that persistence of BU in tissue is prolonged, and that these properties may permit BU to contribute significantly to the antifungal activity of BR.
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U2 - 10.1093/jac/27.6.837
DO - 10.1093/jac/27.6.837
M3 - Article
C2 - 1938690
AN - SCOPUS:0025895216
SN - 0305-7453
VL - 27
SP - 837
EP - 844
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 6
ER -