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Effect of dose and input rate on the brain penetration of BMS‐204352 following intravenous administration to rats
Author(s) -
Krishna Rajesh,
Palme Holly,
Zeng Jianing,
Srinivas Nuggehally
Publication year - 2002
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.317
Subject(s) - pharmacokinetics , bolus (digestion) , jugular vein , intravenous bolus , penetration (warfare) , medicine , pharmacology , anesthesia , chemistry , engineering , operations research
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. Copyright © 2002 John Wiley & Sons, Ltd.