Received for publication May 25, 2005.
Revised June 22, 2005.
Accepted for publication June 22, 2005.

Distribution of the Novel Antifolate Pemetrexed to the Brain

Abstract

Pemetrexed disodium is a novel antifolate which 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 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 were measured by simultaneous arterial blood and frontal cortex microdialysis sampling. In the IV bolus experiments, indomethacin was administered by iv bolus (10mg/kg) followed by iv infusion (0.1mg/kg/hour) in a crossover fashion. In the infusion experiments, the same dose indomethacin was administered after a steady state was reached for pemetrexed. CNS distributional kinetics were analyzed by compartmental and non-compartmental methods. Both bolus and infusion studies showed that pemetrexed has a limited CNS distribution. The mean AUC_brain / AUC_plasma ratio of unbound pemetrexed is 0.078±0.038 in the iv bolus study. The pemetrexed steady-state brain-to-plasma unbound concentration ratio after iv infusion is 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 non-compartmental 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.

Key words: antifolate, blood-brain barrier, brain distribution, efflux transporters, microdialysis, pemetrexed