title: Pharmacokinetics and dose proportionality of BMS-204352 after intraarterial administration to rats.
abstract: 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 rats. In an open, parallel fashion, sixteen rats per gender received a single intraarterial dose of BMS-204352 as a 3-min infusion into the carotid artery at 0.4, 2.0, 5.0 and 10.0 mg/kg dose levels. Serial blood samples were collected for up to 24 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 revealed a gender difference in the pharmacokinetics of BMS-204352 in rats at all doses excluding the first (i.e., 0.4 mg/kg) dose panel. BMS-204352 peak plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) values increased in a proportion greater than the increment in dose. Specifically, as dose increased in the ratio 1:5:12.5:25, C(max) increased in the ratio 1:7:18:31 in male rats and 1:7:22:51 in female rats. The respective AUC ratios were 1:6:20:42 in male rats and 1:12:29:77 in female rats. Mean total body clearance (CL(T)) values for BMS-204352 ranged from 879-3242 ml/h/kg over the four dose levels and generally decreased with increase in dose. Similarly, steady state volume of distribution (V(SS)) values ranged from 3621-8933 ml/kg over the four dose levels and generally decreased with increase in dose. However, mean residence time (MRT) and elimination half-life (T(1/2)) values for BMS-204352 were independent of dose and ranged from 2.42-4.54 to 2.08-4.70 h, respectively. In conclusion, BMS-204352 appears to exhibit dose-dependent pharmacokinetics in rats. In addition, there appeared to be some evidence of gender related differences in the pharmacokinetics of BMS-204352.
authors.affiliation: Clinical Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. rajesh.krishna@bms.com
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
authors.forename: Vinod R
authors.initials: VR
authors.lastname: Shah
authors.forename: Nuggehally
authors.initials: N
authors.lastname: Srinivas
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D007211:Indoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D007269:Injections, Intra-Arterial; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013997:Time Factors
chemical_list: C424388:BMS204352; D007211:Indoles