Pharmacokinetic and metabolism studies on girisopam by chromatographic and spectrometric methods in humans.
Girisopam possesses selective anxiolytic action without muscle relaxant and anticonvulsive activity. After a 100-mg oral dose of 14C-labelled girisopam to seven male subjects, the mean recovery of 14C radioactivity was 51% in urine and 33% in faeces. A high-performance liquid chromatographic method has been developed for studying girisopam in single-dose pharmacokinetic studies. The serum extract was chromatographed on a normal-phase column using a mobile phase of hexane-ethanol-diethyl ether (66:9:25, v/v) and ultraviolet detection at 235 nm. The recovery was 60% and the detection limit was 3 ng/ml, using 1 ml of serum. After a 20-min delay, girisopam is rapidly absorbed. After reaching a mean serum level of 178 ng/ml at a mean time of 2.0 h, the serum concentration of girisopam decreased with a mean elimination half-time of 22.2 h. The metabolites were separated by high-performance liquid chromatography, radio thin-layer chromatography and gas chromatography. Their structures were determined by liquid chromatography-mass spectrometry, mass spectrometry and gas chromatography-mass spectrometry. Their chemical structures were confirmed by comparison with synthesized reference compounds. The major urinary metabolites were 7-demethylgirisopam (I), 4'-hydroxygirisopam (II) and 4-hydroxymethyl-4-demethylgirisopam (III), which were in conjugated form, and 4-carboxy-4-demethylgirisopam (V), a compound with an open-chain structure (VII) and traces of 4-demethyl-4-oxogirisopam (VIII) and 4-hydroxymethyl-4-demethylgirisopam (III), which were in non-conjugated form. The metabolic profile in the serum consisted predominantly of the glucuronides of I, II and III. The non-conjugated metabolites were the metabolite with the open-chain structure (VII), III and V. Besides the parent compound, the faeces sample contained conjugates of I and II.
Tomori
E
E
Institute for Drug Research, Budapest, Hungary.
Horváth
G
G
Pátfalusi
M
M
Mészáros
S
S
Vereczkey
L
L
D000328:Adult; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000302:isolation & purification / Q000378:metabolism / Q000493:pharmacokinetics*; D002845:Chromatography / Q000379:methods*; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005243:Feces / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008875:Middle Aged; D015203:Reproducibility of Results
D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; C045445:girisopam