Microsomal catalyzed N-hydroxylation of guanfacine and reduction of N-hydroxyguanfacine.
Guanfacine 1 is a well known centrally acting alpha 2-adrenoceptor agonist with antihypertensive activity. The drug belongs to the guanidine class of compounds. The N-oxidative biotransformation of guanfacine was investigated in vitro in the presence of hepatic microsomal fractions from rabbits, pigs, and humans. The N-hydroxylated derivative N-hydroxyguanfacine 2 had to be synthesized as reference for the identification of the metabolite. The corresponding in vitro retroreduction of N-hydroxyguanfacine 2 was also investigated using the same set of enzyme sources. A new HPLC analytical method was developed in order to isolate and quantify the metabolites. A complete metabolic cycle involving the oxidative metabolism of guanfacine could only be observed in the presence of microsomal fractions from rabbitt livers, whereas enzyme sources of all species under investigation catalyzed the N-reduction of N-hydroxyguanfacine 2.
Clement
B
B
Pharmazeutisches Institut, Christian-Albrechts-Universität Kiel, Germany.
Demesmaeker
M
M
D000316:Adrenergic alpha-Agonists / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005260:Female; D016316:Guanfacine / Q000378:metabolism* / Q000493:pharmacokinetics; D006146:Guanidines / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010084:Oxidation-Reduction; D011817:Rabbits; D013552:Swine
D000316:Adrenergic alpha-Agonists; D000959:Antihypertensive Agents; D006146:Guanidines; D016316:Guanfacine; C036646:3-hydroxyguanfacine; D006899:Mixed Function Oxygenases