title: Histamine H1-receptor antagonists, promethazine and homochlorcyclizine, increase the steady-state plasma concentrations of haloperidol and reduced haloperidol.
abstract: The effects of histamine H1-receptor antagonists, promethazine and homochlorcyclizine, both of which are inhibitors of CYP2D6, on the steady-state plasma concentrations (Css) of haloperidol and reduced haloperidol were studied in 23 schizophrenic inpatients receiving haloperidol, 12 to 36 mg/d, for 2 to 29 weeks. Promethazine, 150 mg/d, in 11 patients and homochlorcyclizine, 60 mg/d, in the others were coadministered for at least 1 week. Blood sampling was performed before and during coadministration of promethazine or homochlorcyclizine and 1 week after the discontinuation, together with clinical assessments by Brief Psychiatric Rating Scale (BPRS) and Udvalg for kliniske undersogelser (UKU) side effect rating scale. The Css (mean +/- SD) of haloperidol and reduced haloperidol during promethazine coadministration (27.6 +/- 24.9 and 8.6 +/- 13.2 ng/mL) were significantly higher than those before the coadministration (12.7 +/- 10.8 and 5.0 +/- 6.0 ng/mL; P < 0.01) or 1 week after the discontinuation (15.6 +/- 14.8 and 5.8 +/- 7.9 ng/mL; P < 0.05). The Css of haloperidol and reduced haloperidol during homochlorcyclizine coadministration (14.9 +/- 8.1 and 6.4 +/- 5.4 ng/mL) were also significantly higher than those before the coadministration (10.9 +/- 7.2 and 3.8 +/- 3.6 ng/mL; P < 0.01) or 1 week after the discontinuation (12.9 +/- 7.4 and 4.8 +/- 4.1 ng/mL; P < 0.05). No change in BPRS or UKU score was found throughout the study. Thus, the current study suggests that coadministration of clinical doses of promethazine and homochlorcyclizine increases the Css of haloperidol and reduced haloperidol via the inhibitory effects on the CYP2D6-catalyzed metabolism of haloperidol and reduced haloperidol.
authors.affiliation: Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Suzuki
authors.forename: Norio
authors.initials: N
authors.lastname: Yasui-Furukori
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mihara
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Hanako
authors.initials: H
authors.lastname: Furukori
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Inoue
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
authors.forename: Koichi
authors.initials: K
authors.lastname: Otani
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000097:blood* / Q000493:pharmacokinetics; D003501:Cyclizine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011398:Promethazine / Q000494:pharmacology*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D006634:Histamine H1 Antagonists; C040692:4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanol; D011398:Promethazine; D006220:Haloperidol; C034022:homochlorocyclizine; D003501:Cyclizine