Determination of the dopamine D2 agonist N-0923 and its major metabolites in perfused rat livers by HPLC-UV-atmospheric pressure ionization mass spectrometry.
The metabolism of the dopamine D2 agonist N-0923 was investigated by an in vitro isolated liver perfusion. Determining the metabolic profile and identity of the different metabolites was achieved by using high-performance liquid chromatography with UV detection, combined with atmospheric pressure ionization mass spectrometry. Using this technique, no extensive sample cleanup is required, and the studies can be performed without radioactivity. In addition to previously observed metabolites, nine new metabolic products were identified. All metabolites were exclusively excreted into the bile, except for the despropyl metabolite, which was also detectable in the perfusate. 5-O-Glucuronidation and N-depropylation followed by 5-O-glucuronidation are the most important metabolic routes. N-dealkylation of the thienylethyl group followed by 5-O-glucuronidation and sulfation is a second major metabolic pathway. Catechol formation of the despropyl metabolite with or without subsequent conjugation was not found. Catechol formation of the desthienylethyl metabolite occurred, but only its glucuronide conjugates were found. This study complements previous results of in vivo metabolic studies using the radiolabeled racemate N-0437, and it explains differences in bile excretion during isolated liver perfusions using N-0923 and radiolabeled N-0923.
Swart
P J
PJ
Department of Analytical Chemistry and Toxicology, University Centre for Pharmacy, Groningen, The Netherlands.
Oelen
W E
WE
Bruins
A P
AP
Tepper
P G
PG
de Zeeuw
R A
RA
D000818:Animals; D001646:Bile / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D015259:Dopamine Agents / Q000032:analysis* / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000737:chemistry*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet; D013764:Tetrahydronaphthalenes / Q000032:analysis* / Q000378:metabolism; D013876:Thiophenes / Q000032:analysis* / Q000378:metabolism
D015259:Dopamine Agents; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine