Enhanced bioavailability of oral docetaxel by co-administration of cyclosporin A in dogs and rats.
Pharmacokinetic and pharmacodynamic endpoints of intravenously and orally administered docetaxel (DT) with or without oral cyclosporine were characterized in rats and dogs. Plasma samples were analysed for DT using liquid chromatography-mass spectrometry. DT area-under-the-concentration-time curve, plasma clearance and maximum serum clearance were significantly affected by cyclosporine in rats (P <or= 0.0005). Bioavailability of DT alone and DT combined with cyclosporine was 1.3 and 82%, respectively, in rats. In dogs, cyclosporine resulted in a 14-17-fold increase in peak DT concentrations (P < 0.0005) and area-under-the-curve (P < 0.0005), and a 17-fold reduction in DT clearance (P < 0.005). Bioavailability of DT alone was 18 +/- 16% and statistically exceeded 100% (251 +/- 104%) when combined with cyclosporine in dogs. Two of the six dogs receiving DT plus cyclosporine developed neutropenia, and one of the six dogs experienced vomiting and diarrhoea. Cyclosporine significantly alters the disposition of oral DT in dogs and rats, such that clinically relevant serum concentrations are achievable.
McEntee
M
M
College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA.
Silverman
J A
JA
Rassnick
K
K
Zgola
M
M
Chan
A O
AO
Tau
P T
PT
Page
R L
RL