Pharmacokinetics of SNX-111, a selective N-type calcium channel blocker, in rats and cynomolgus monkeys.
SNX-111, a selective N-type voltage-sensitive calcium channel blocker, is in clinical trials for the treatment of ischemia-induced brain injury and chronic pain. Pharmacokinetic studies were conducted in rats and cynomologus monkeys to determine the disposition of this compound when it is administered for 24 hr by continuous, constant-rate intravenous infusion. Venous blood samples for determination of SNX-111 plasma levels were collected at regular intervals immediately before, during, and after dosing. Plasma concentrations of SNX-111 equivalents were measured by radioimmunoassay. Pharmacokinetic parameters were derived from plasma SNX-111 concentration-time data using a two-compartment pharmacokinetic model. Results showed close correspondences between pharmacokinetic parameters determined for both species. There were no consistent gender- or dose-related differences in calculated kinetic parameters. In all cases, apparent steady-state plasma SNX-111 concentrations were achieved within 2-4 hr of initiating SNX-111 infusion. Steady-state volume of distribution values were approximately 40% of body weight, indicating extravascular dissemination of SNX-111 to both extracellular and intracellular fluids. Elimination curves contained two exponential components. The fast component (rat t1/2, alpha = 0.375 hr; monkey t1/2, alpha = 0.730 hr) accounted for approximately 97% of the unit impulse disposition function. The apparent terminal half-life ranged from 4.61 hr (rat) to 6.48 hr (monkey). Current findings constitute the first description of the pharmacokinetics of a member of the omega-conopeptide family of neuronal calcium channel blockers.
Bowersox
S
S
Department of Pharmacology, Neurex Corporation, Menlo Park, CA 94025-1012, USA.
Mandema
J
J
Tarczy-Hornoch
K
K
Miljanich
G
G
Luther
R R
RR
D000818:Animals; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D010455:Peptides; D020960:omega-Conotoxins; C078452:ziconotide