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Pharmacokinetics and dose proportionality of BMS‐204352 after intravenous administration to dogs
Author(s) -
Krishna Rajesh,
Shah Vinod R.,
Mantha Subbaro,
Vachharajani Nimish N.,
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.294
Subject(s) - pharmacokinetics , beagle , half life , volume of distribution , washout , dose , chemistry , pharmacology , medicine , nuclear medicine , anesthesia
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 dose proportionality and pharmacokinetics of BMS‐204352 in dogs. In an open, three‐way crossover study, three beagle dogs received a single intravenous dose of BMS‐204352 as a 6‐min infusion into the femoral vein at 0.4, 0.9, and 2.0 mg/kg dose levels. There was at least a 1‐week washout period between treatments. Serial blood samples were collected for up to 32 h post dose and plasma samples were analyzed for the concentrations of intact BMS‐204352 using a validated liquid chromatographic mass spectrometric (LC/MS) method. Pharmacokinetic analysis was performed using a non‐compartmental method. Results indicated that peak BMS‐204352 concentrations ( C max ) and area under the plasma concentration–time curves (AUC) values increased in a dose proportional manner. Mean residence time (MRT, 18.2–21.9 h) and elimination half‐life ( T half , 13.5–17 h) did not change with dose. There was no dose dependency in the mean BMS‐204352 total body clearance (CLT, 134–158 ml/h/kg) and mean steady state volume of distribution (VSS, 2839‐3291 ml/kg). The high VSS value indicated that BMS‐204352 was distributed extensively in the extravascular tissues. In conclusion, BMS‐204352 exhibits linear pharmacokinetics over the dose range tested (0.4–2 mg/kg). Copyright © 2002 John Wiley & Sons, Ltd.