RT Journal Article
SR Electronic
T1 CYTOCHROME P450 3A-MEDIATED METABOLISM OF BUSPIRONE IN HUMAN LIVER MICROSOMES
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 500
OP 507
DO 10.1124/dmd.104.000836
VO 33
IS 4
A1 Zhu, Mingshe
A1 Zhao, Weiping
A1 Jimenez, Humberto
A1 Zhang, Donglu
A1 Yeola, Suresh
A1 Dai, Renke
A1 Vachharajani, Nimish
A1 Mitroka, James
YR 2005
UL http://dmd.aspetjournals.org/content/33/4/500.abstract
AB This study was carried out to determine the metabolic pathways of buspirone and cytochrome P450 (P450) isoform(s) responsible for buspirone metabolism in human liver microsomes (HLMs). Buspirone mainly underwent N-dealkylation to 1-pyrimidinylpiperazine (1-PP), N-oxidation on the piperazine ring to buspirone N-oxide (Bu N-oxide), and hydroxylation to 3′-hydroxybuspirone (3′-OH-Bu), 5-hydroxybuspirone (5-OH-Bu), and 6′-hydroxybuspirone (6′-OH-Bu) in HLMs. The apparent Km values for buspirone metabolite formation in pooled HLMs were 8.7 (1-PP), 34.0 (Bu N-oxide), 4.3 (3′-OH-Bu), 11.4/514 (5-OH-Bu), and 8.8 μM (6′-OH-Bu). CYP3A inhibitor ketoconazole (1 μM) completely inhibited the formation of all major metabolites in HLMs (0-16% of control), whereas the chemical inhibitor selective to other P450 isoforms had little or no inhibitory effect. Recombinant CYP3A4, CYP3A5, and CYP2D6 exhibited buspirone oxidation activities among nine P450 isoforms tested. The overall metabolism rate of 5 μM buspirone by CYP3A4 was 18-fold greater than that by CYP2D6 and 35-fold greater than that by CYP3A5. In a panel of HLMs from 16 donors, buspirone metabolism correlated well CYP3A activity (r2 = 0.85-0.96, ρ < 0.0005), but not the activities of other P450 isoforms. The metabolism rates of buspirone in CYP2D6 poor-metabolizer genotype HLMs were comparable to those in pooled HLMs. Taken together, these data suggest that CYP3A, mostly likely CYP3A4, is primarily responsible for the metabolism of buspirone in HLMs. The American Society for Pharmacology and Experimental Therapeutics