Pemetrexed disodium is a novel
antifolate that exhibits potent inhibitory effects on multiple
enzymes in
folate metabolism. Phase II/III clinical trials have shown that
pemetrexed is effective against various solid
tumors. Like
methotrexate,
pemetrexed may be useful in treatment of primary and secondary
brain tumors. In this study, we examined the central nervous system (CNS) distribution of
pemetrexed and the interaction with an organic
anion transport inhibitor
indomethacin. Male Wistar rats were administered
pemetrexed by either single intravenous bolus or constant
intravenous infusion. Unbound
pemetrexed in blood and brain was measured by simultaneous arterial blood and frontal cortex microdialysis sampling. In the i.v. bolus experiments,
indomethacin was administered by i.v. bolus (10 mg/kg) followed by i.v. infusion (0.1 mg/kg/h) in a crossover manner. In the infusion experiments, the same dose of
indomethacin was administered after a steady state was reached for
pemetrexed. CNS distributional kinetics was analyzed by compartmental and noncompartmental methods. Both bolus and infusion studies showed that
pemetrexed has a limited CNS distribution. The mean area under concentration-time curve (AUC)(brain)/AUC(plasma) ratio of unbound
pemetrexed was 0.078 +/- 0.038 in the i.v. bolus study. The
pemetrexed steady-state brain-to-plasma unbound concentration ratio after i.v. infusion was 0.106 +/- 0.054. The distributional clearance into the brain was approximately 10% of the clearance out of the brain in both the compartmental and noncompartmental analyses.
Indomethacin had no effect on either the brain-to-plasma AUC ratio or the steady-state brain-to-plasma concentration ratio. The distribution of
pemetrexed into the brain is limited, and an efflux clearance process, such as an efflux transporter, may be involved.