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Methods and Findings
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Methods Find Exp Clin Pharmacol 2005, 27(2): 83
ISSN 0379-0355
Copyright 2005 Clarivate Analytics
CCC: 0379-0355
DOI: 10.1358/mf.2005.27.2.876282
Metabolic mechanism of quetiapine in vivo with clinical therapeutic dose
Li, k.-Y., Li, X., Cheng, Z.N., Li, H.D.
The in vivo metabolic mechanism of quetiapine (QTP) with clinical therapeutic dose was studied. Nineteen patients received multiple doses of QTP with or without concomitant erythromycin. Midazolam was given to detect enzyme activity. Plasma Concentrations of QTP, midazolam, and their metabolites were measured at specified time intervals. In presence of erythromycin, activity of CYP3A4 decreased significantly; for QTP, Cmax, AUC0-24, and t1/2 increased significantly, CL decreased significantly, and variations in AUC0-24 and CL showed, respectively, significant negative and positive correlation to that of CYP3A4 activity; for QTP sulfoxide (QTP-SF), Cmax and AUC0-24 decreased significantly, t1/2 increased significantly, and variation of t1/2 was significantly positively correlated to that of CYP3A4 activity; for 7-hydroxy-quetiapine (QTP-H), t1/2 increased significantly and was closely correlated to CYP3A4 activity; for 7-hydroxy-N-desalkyl-quetiapine (QTP-ND), Cmax and AUC0-24 decreased significantly, and variation of AUC0-24 was significantly positively correlated to that of CYP3A4 activity. In conclusion, the major metabolic pathway of QTP is sulfoxidation. CYP3A4 is the primary enzyme responsible for CYP-mediated metabolism of QTP in clinical therapy dosage in vivo. QTP sulfoxidation and N-dealkylation are mainly catalyzed by CYP3A4. 7-Hydroxylation of QTP is not mainly catalyzed by CYP3A4. The metabolism of QTP-SF and QTP-H is mainly catalyzed by CYP3A4, but QTP-ND is not by CYP3A4.

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