RT Journal Article
SR Electronic
T1 Identification of the Cytochrome P450 and other Enzymes Involved in the In Vitro Oxidative Metabolism of a Novel Antidepressant, Lu AA21004
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.112.044610
DO 10.1124/dmd.112.044610
A1 Mette G. Hvenegaard
A1 Benny Bang-Andersen
A1 Henrik Pedersen
A1 Morten Jorgensen
A1 Ask Puschl
A1 Lars Dalgaard
YR 2012
UL http://dmd.aspetjournals.org/content/early/2012/04/11/dmd.112.044610.abstract
AB Lu AA21004 (1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine) is a novel antidepressant and is currently in late stage clinical development for major depressive disorder. In the present study, the metabolism of Lu AA21004 was investigated using human liver microsomes, human liver S9-fraction and recombinant enzymes. Lu AA21004 was found in vitro, to be oxidised to a 4-hydroxy-phenyl metabolite, a sulfoxide, an N-hydroxylated piperazine and a benzylic alcohol, which was further oxidised to the corresponding benzoic acid (Lu AA34443). The formation of the 4-hydroxy-phenyl metabolite was catalysed by CYP2D6 with some contribution from CYP2C9, whereas the formation of the sulfoxide was mediated by CYP3A4/5 and CYP2A6. CYP2C9 and CYP2C19 were the primary enzymes responsible for formation of the N-hydroxylated metabolite. The benzylic alcohol was formed by CYP2D6 only. The oxidation of the benzylic alcohol to the corresponding benzoic acid of Lu AA21004 was catalysed by alcohol dehydrogenase and aldehyde dehydrogenase, with some contribution from aldehyde oxidase. CYP2D6 was also capable of catalyzing the formation of the benzoic acid of Lu AA21004; however, its overall contribution to this pathway was negligible. Enzyme kinetic parameters revealed that the rate-limiting step in the formation of the benzoic acid from Lu AA21004 is the formation of the corresponding alcohol. Thus, the intrinsic clearance (Vmax/Km) in HLM for metabolism of Lu AA21004 to the benzylic alcohol was 1.13 x 10-6 L/min/mg, whereas the subsequent metabolism of the benzylic alcohol to the benzoic acid of Lu AA21004 is characterised by an intrinsic clearance (Vmax/Km) in S9 fraction of 922 x 10-6 L/min/mg.