Pharmacokinetics of pinokalant, a new nonselective cation channel blocker in the rat

• Published in: Arzneimittel-Forschung Vol. 51; no. 12; p. 947
• Main Authors: Leusch, A, Eichhorn, B, Busch, U, Ensinger, H A
• Format: Journal Article
• Language: English
• Published: Germany 01.01.2001
• Subjects: Acetamides - pharmacokinetics; Animals; Bile - metabolism; Blood Proteins - metabolism; Blood-Brain Barrier; Brain Injuries - metabolism; Chromatography, High Pressure Liquid; Feces - chemistry; Female; Injections, Intravenous; Ion Channels - antagonists & inhibitors; Isoquinolines - pharmacokinetics; Male; Middle Cerebral Artery - metabolism; Protein Binding; Rats; Spectrometry, Fluorescence
• ISSN: 0004-4172
• DOI: 10.1055/s-0031-1300143

The pharmacokinetics of 1-isoquinolineacetamide, 3,4-dihydro-6,7-dimethoxy-alpha-phenyl-N,N-bis [2-(2,3,4-trimethoxyphenyl)ethyl]-, monomethanesulfonate (pinokalant, salt form of the active entity LOE 908 BS, CAS 143482-63-7), a nonselective cation channel blocker, was studied in rats. Drug plasma levels declined rapidly in a polyphasic manner after intravenous bolus administration of 8.8 mg/kg LOE 908 BS. The disposition of LOE 908 BS was governed by a rapid elimination (clearance Cl = 47.7 ml/min/kg) and an extensive distribution into tissues (volume of distribution Vss = 7.21 l/kg). A dose-proportional increase of AUC and steady state concentration up to doses of 194 mg/kg (6 h infusion) was observed suggesting linear pharmacokinetics. The protein binding was very high with 99.4% to 99.7% bound to plasma proteins in the concentration range 0.26 to 2.6 micrograms/ml. The LOE 908 BS concentration-time profile in brain tissue after intravenous infusion (4.4 mg/kg/h over 4 h) paralleled those measured in plasma indicating a rapid but also low penetration of the blood-brain-barrier. The concentration-time profile of drug-related radioactivity after intravenous (bolus) administration of [14C]LOE 908 BS dropped also rapidly to approximately 16% within the first hour compared to the initial 2-min value. The drug exhibited a high biliary excretion (84% during 5 h) and, accordingly, faecal excretion was the main route of excretion (> 90%). The mass balance was complete after 96 h indicating no persistence of radioactivity in the animals. The relevance of these findings with respect to results obtained with LOE 908 BS in animal models for stroke and traumatic brain injury is discussed.