PMID- 35853541
OWN - NLM
STAT- MEDLINE
DCOM- 20220816
LR  - 20220816
IS  - 1872-7786 (Electronic)
IS  - 0009-2797 (Linking)
VI  - 364
DP  - 2022 Sep 1
TI  - Pharmacokinetic interactions between clozapine and valproic acid in patients with 
      treatment-resistant schizophrenia: Does UGT polymorphism affect these drug 
      interactions?
PG  - 110042
LID - S0009-2797(22)00247-2 [pii]
LID - 10.1016/j.cbi.2022.110042 [doi]
AB  - The combination of valproic acid (VPA) and clozapine (CLZ) is regularly 
      prescribed for augmentation therapy in treatment resistant schizophrenia. The VPA 
      has been shown to reduce norclozapine (NCLZ) plasma levels, but the mechanism of 
      this interaction remains unknown. The aim of this study is to examine the 
      differences between patients treated with CLZ and patients treated with CLZ plus 
      VPA. For it, various factors have been evaluated. The study was based on plasma 
      samples from CLZ and CLZ plus VPA treated patients (n = 61) subjected to routine 
      therapeutic drug monitoring considering clinical data, smoking status, daily dose 
      of CLZ and VPA, concomitant medications, albumin, and renal and hepatic function. 
      Genotyping of polymorphisms of CYP1A2, CYP3A4/5, CYP2C19, ABCB1, UGT2B10 and 
      CYP2C19 were performed by real time PCR. CYP2D6 were genotyped using competitive 
      allele-specific PCR and by a long PCR based method. Plasma CLZ and NCLZ 
      concentrations were measured by Liquid Chromatography-Tandem masses (LC-MS/MS) 
      and plasma VPA by Ultraviolet-Visible (UV-vis) spectrophotometric immunoassay. 
      The patients presented adequate CLZ levels in relation to the dose. However, NCLZ 
      levels were excessively low and the CLZ/NCLZ ratio very high. Patients with 
      UGT2B10 GT (rs61750900) genotype showed lower NCLZ plasma levels and C/D NCLZ, 
      and higher CLZ/NCLZ ratio versus patients with UGT2B10 GG genotype. VPA, smoking, 
      the presence of UGT2B10 GT genotype and having low albumin levels indicate that 
      the CLZ/NCLZ ratio is affected, mostly coinciding with decreased NCLZ levels and 
      possibly with an increased risk of neutropenia.
CI  - Copyright (c) 2022 Elsevier B.V. All rights reserved.
FAU - Sanguesa, Estela
AU  - Sanguesa E
AD  - Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gallego- 
      Zaragoza, Spain.
FAU - Cirujeda, Christine
AU  - Cirujeda C
AD  - Centro Neuropsiquiatrico Nuestra Senora del Carmen, Hermanas Hospitalarias, 
      Zaragoza, Spain.
FAU - Concha, Julia
AU  - Concha J
AD  - Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gallego- 
      Zaragoza, Spain.
FAU - Padilla, Pedro Pablo
AU  - Padilla PP
AD  - Centro Neuropsiquiatrico Nuestra Senora del Carmen, Hermanas Hospitalarias, 
      Zaragoza, Spain.
FAU - Garcia, Cristina Belen
AU  - Garcia CB
AD  - Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gallego- 
      Zaragoza, Spain. Electronic address: cbgarcia@usj.es.
FAU - Ribate, Maria Pilar
AU  - Ribate MP
AD  - Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gallego- 
      Zaragoza, Spain.
LA  - eng
PT  - Journal Article
DEP - 20220716
PL  - Ireland
TA  - Chem Biol Interact
JT  - Chemico-biological interactions
JID - 0227276
RN  - 0 (Albumins)
RN  - 0 (Antipsychotic Agents)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2C19)
RN  - EC 2.4.1.- (UGT2B10 protein, human)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - J60AR2IKIC (Clozapine)
SB  - IM
MH  - Albumins
MH  - *Antipsychotic Agents/therapeutic use
MH  - Chromatography, Liquid
MH  - *Clozapine/therapeutic use
MH  - Cytochrome P-450 CYP2C19
MH  - Drug Interactions
MH  - Glucuronosyltransferase/genetics
MH  - Humans
MH  - *Schizophrenia/drug therapy/genetics
MH  - Schizophrenia, Treatment-Resistant
MH  - Tandem Mass Spectrometry
MH  - Valproic Acid/therapeutic use
EDAT- 2022/07/20 06:00
MHDA- 2022/08/17 06:00
CRDT- 2022/07/19 19:24
PHST- 2022/06/20 00:00 [received]
PHST- 2022/07/13 00:00 [accepted]
PHST- 2022/07/20 06:00 [pubmed]
PHST- 2022/08/17 06:00 [medline]
PHST- 2022/07/19 19:24 [entrez]
AID - S0009-2797(22)00247-2 [pii]
AID - 10.1016/j.cbi.2022.110042 [doi]
PST - ppublish
SO  - Chem Biol Interact. 2022 Sep 1;364:110042. doi: 10.1016/j.cbi.2022.110042. Epub 
      2022 Jul 16.