Pharmacokinetics of two partial benzodiazepine receptor agonistic beta-carboline derivatives in healthy volunteers.
Plasma levels of the two beta-carboline derivatives, ZK 91,296 (ethyl 5-benzyloxy-4-methoxymethyl-9H-pyrido (3,4-b) indole-3-carboxylate, CAS 83910-34-3) and ZK 95,962 (ethyl 5-isopropoxy-4-methoxymethyl-9H-pyrido (3,4-b) indole-3-carboxylate, CAS 101071-43-6) were measured in a total of 46 healthy male volunteers. The doses ranged from 1 to 40 micrograms/kg injected intravenously and from 40 to 600 mg given orally. Following i.v. injection, plasma levels declined in two phases with half-lives of 2-4 min (both drugs) and 0.5 h (ZK 95,962) or 1 h (ZK 91,296). The total clearance was 40-50 ml/min/kg and the oral bioavailability was estimated to be below 1% for both compounds. The reason was rapid first-pass inactivation, probably in the liver, and the formation of an acid metabolite. The plasma levels of this substance, which were determined after oral administration of ZK 91,296, were linearly correlated with the dose.
Research Laboratories, Schering Aktiengesellschaft, Berlin (Fed. Rep. of Germany.
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Krause
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Dorow
D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001682:Biological Availability; D002243:Carbolines / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D008297:Male; D011963:Receptors, GABA-A / Q000187:drug effects*; D013050:Spectrometry, Fluorescence
D000927:Anticonvulsants; D002243:Carbolines; D011963:Receptors, GABA-A; C063837:ZK 95962; C038933:ZK 91296; C062769:abecarnil