PT  - JOURNAL ARTICLE
AU  - Dai, Haiqing
AU  - Chen, Ying
AU  - Elmquist, William F.
TI  - Distribution of the Novel Antifolate Pemetrexed to the Brain
AID  - 10.1124/jpet.105.090043
DP  - 2005 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 222--229
VI  - 315
IP  - 1
4099  - http://jpet.aspetjournals.org/content/315/1/222.short
4100  - http://jpet.aspetjournals.org/content/315/1/222.full
SO  - J Pharmacol Exp Ther2005 Oct 01; 315
AB  - 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/AUCplasma 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. The American Society for Pharmacology and Experimental Therapeutics