Effect of dose and input rate on the brain penetration of BMS-204352 following intravenous administration to rats

BMS-204352 is a novel maxi-K channel opener that is being developed for the treatment for stroke. The current study was designed to evaluate the plasma and brain pharmacokinetics of BMS-204352 in rats, in particular, assessing the effect of dose and input rate on brain penetration of BMS-204352. Rats (3 animals/group/time point) received a single intravenous dose of BMS-204352 as 5 mg/kg bolus, 5 mg/kg 30 min infusion, 5 mg/kg 60 min infusion, and 10 mg/kg bolus dose, into the jugular vein. Terminal blood (for plasma) and brain samples were collected for up to 9 h post-dose and samples were analyzed for the concentrations of intact BMS-204352 using a validated liquid chromatographic tandem mass spectrometric method (LC/MS/MS). As dose increased from 5 to 10 mg/kg, both BMS-204352 C(max) and AUC values increased in plasma and brain, somewhat greater in proportion to the increment in dose. Whereas the peak concentrations of BMS-204352 were affected by infusion time, overall AUCs were comparable across the bolus and infusion groups. Terminal disposition (T-half ranged from 1.6 to 2.7 h) of BMS-204352 was unaltered as a function of input rate. BMS-204352 crossed the blood-brain barrier with brain-to-plasma (B/P) ratios of approximately 7-11. Brain-to-plasma ratios appeared to be independent of dose and infusions produced somewhat higher brain penetration (B/P of ca. 11) as compared to bolus (B/P of ca. 7-8) dose. The decline of BMS-204352 in the brain paralleled that of plasma independent of the input rate and dose.