Abstract
The effect of cefoperazone (CPZ) on the pharmacokinetics of methotrexate (MTX) was studied in 10 rabbits. MTX was administered as a bolus dose of 2 mg kg
−1, followed by a constant infusion of 50 μg kg
−1 min
−1 for 120 min. A group of 5 rabbits received, concomitantly, 20 mg kg
−1 CPZ every 30 min, begining at MTX administration. Blood samples were serially collected for a total period of 320 min post infusion, and plasma was analyzed for MTX using high performance liquid chromatography (HPLC). The mean (± SD) values of the pharmacokinetic parameters were as follows: total area under the curve (AUC) 967 ± 704, 1801 ± 778 μg min 1
−1; steady state MTX concentration
C
ss, 6.2 ± 4.1, 9.9 ± 3.6 μg ml
−1; and maximum plasma concentration (C
p
max) 7.5 ± 4.5, 24.2 ± 11.2μg ml
−1 for the single and drug combination groups, respectively. The differences in these parameters were statistically significant (
p < 0.02). The corresponding estimates of elimination half-lives (
t
1
2
) were 60 ± 21.6 and 53.3 ± 8.5 min, and the difference in the value of this parameter between the treatment groups did not reach statistical significance (
p > 0.05). These results suggest that CPZ may influence the distribution phase, rather than the elimination stage, of MTX disposition in rabbits. The results of the present study may have relevance to a potential interaction that can exist between these drugs when administered concurrently in humans. However, further studies in appropriate subjects are needed to verify and characterize the clinical significance of such an interaction.