Pharmacokinetics and dose proportionality of BMS-204352 after intravenous administration to dogs. 2002

Rajesh Krishna, and Vinod R Shah, and Subbaro Mantha, and Nimish N Vachharajani, and Nuggehally Srinivas
Clinical Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. rajesh.krishna@bms.com

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).

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D007275 Injections, Intravenous Injections made into a vein for therapeutic or experimental purposes. Intravenous Injections,Injection, Intravenous,Intravenous Injection
D008297 Male Males
D004285 Dogs The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065) Canis familiaris,Dog
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015221 Potassium Channels Cell membrane glycoproteins that are selectively permeable to potassium ions. At least eight major groups of K channels exist and they are made up of dozens of different subunits. Ion Channels, Potassium,Ion Channel, Potassium,Potassium Channel,Potassium Ion Channels,Channel, Potassium,Channel, Potassium Ion,Channels, Potassium,Channels, Potassium Ion,Potassium Ion Channel
D018696 Neuroprotective Agents Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. Neuroprotectant,Neuroprotective Agent,Neuroprotective Drug,Neuroprotectants,Neuroprotective Drugs,Neuroprotective Effect,Neuroprotective Effects,Agent, Neuroprotective,Agents, Neuroprotective,Drug, Neuroprotective,Drugs, Neuroprotective,Effect, Neuroprotective,Effects, Neuroprotective
D019540 Area Under Curve A statistical means of summarizing information from a series of measurements on one individual. It is frequently used in clinical pharmacology where the AUC from serum levels can be interpreted as the total uptake of whatever has been administered. As a plot of the concentration of a drug against time, after a single dose of medicine, producing a standard shape curve, it is a means of comparing the bioavailability of the same drug made by different companies. (From Winslade, Dictionary of Clinical Research, 1992) AUC,Area Under Curves,Curve, Area Under,Curves, Area Under,Under Curve, Area,Under Curves, Area

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