title: Metabolic mechanism of quetiapine in vivo with clinical therapeutic dose.
abstract: 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, C(max), AUC(0-24), and t(1/2) increased significantly, CL decreased significantly, and variations in AUC(0-24) and CL showed, respectively, significant negative and positive correlation to that of CYP3A4 activity; for QTP sulfoxide (QTP-SF), C(max) and AUC(0-24) decreased significantly, t(1/2) increased significantly, and variation of t(1/2) was significantly positively correlated to that of CYP3A4 activity; for 7-hydroxy-quetiapine (QTP-H), t(1/2) increased significantly and was closely correlated to CYP3A4 activity; for 7-hydroxy-N-desalkyl-quetiapine (QTP-ND), C(max) and AUC(0-24) decreased significantly, and variation of AUC(0-24) 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.
authors.affiliation: Clinical Pharmaceutical Research Institute, XiangYa Second Hospital, Central South University, Changsha, Hunan 410078, China. Lkunyan@tom.com
authors.forename: K-Y
authors.initials: KY
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: Z-N
authors.initials: ZN
authors.lastname: Cheng
authors.forename: H-D
authors.initials: HD
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003987:Dibenzothiazepines / Q000097:blood / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004917:Erythromycin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D000069348:Quetiapine Fumarate; D012559:Schizophrenia / Q000201:enzymology
chemical_list: D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D003987:Dibenzothiazepines; D004791:Enzyme Inhibitors; D000069348:Quetiapine Fumarate; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam