Sotalol controlled-release systems for arrhythmias: in vitro characterization, in vivo drug disposition, and electrophysiologic effects.
An array of controlled-release formulations of sotalol were investigated for epicardial drug delivery in short-term and chronic long-term treatment models with dogs. A nondegradable matrix formulation of sotalol made with polyurethane was studied by use of short-term treatment model with dogs, and the electrophysiologic effects were compared with those resulting from an intravenous dose of 2 mg/kg of body weight. Epicardial sotalol-polyurethane matrices were also used in 7-day canine implant studies. A sotalol-silicone rubber matrix was used in 60-day epicardial canine implant studies. A biodegradable poly(dl-lactide-co-glycolide) (PLGA) microsphere formulation of sotalol was also studied as a pericardial injection in another series involving 30-day dog experiments. The short-term treatment electrophysiologic effects observed with the epicardial (left ventricular) implantation of a sotalol-polyurethane matrix formulation were comparable to those observed with intravenous sotalol. However, the total dose delivered by the matrix over a 2-h experimental period was 25 times smaller than the intravenous dose (0.077 versus 2 mg/kg). Furthermore, coronary venous sotalol levels after sotalol-polyurethane matrix implantation were in the therapeutic range (1812.4 +/- 415.1 ng/mL), whereas simultaneous peripheral venous levels were more than 1 order of magnitude lower (149.8 +/- 14.1 ng/mL). An intravenous bolus administration of sotalol (2 mg/kg) resulted in coronary venous levels (1537.1 +/- 44.6 ng/mL) that were very close to simultaneous peripheral venous levels (1428.6 +/- 63.9 ng/mL).(ABSTRACT TRUNCATED AT 250 WORDS)
Labhasetwar
V
V
Department of Pediatrics, University of Michigan, Ann Arbor 48109.
Underwood
T
T
Gallagher
M
M
Murphy
G
G
Langberg
J
J
Levy
R J
RJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004285:Dogs; D004594:Electrophysiology; D007275:Injections, Intravenous; D019344:Lactic Acid; D008297:Male; D008863:Microspheres; D009206:Myocardium / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects; D010316:Particle Size; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D011140:Polyurethanes; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D012826:Silicone Elastomers; D012995:Solubility; D013015:Sotalol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D003692:Delayed-Action Preparations; D011108:Polymers; D011140:Polyurethanes; D012826:Silicone Elastomers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D013015:Sotalol