Hydroxyzine and Metabolites as a Source of Interference in Carbamazepine Particle-Enhanced Turbidimetric Inhibition Immunoassay (PETINIA)

Abstract

A 32-year-old epileptic patient with a lengthy history of multiple-drug abuse and psychotic disorders was found to have an elevated serum carbamazepine concentration of 40.5 mg/L (therapeutic range 4-12 mg/L) using particle-enhanced turbidimetric inhibition immunoassay (PETINIA). Serum reanalysis by LC-DAD revealed only high hydroxyzine (HDZ) concentration (HDZ = 0.55 mg/L; therapeutic range <0.1 mg/L), suggesting cross-reactivity between HDZ and PETINIA. To confirm this hypothesis, the authors tested 2 commercially available carbamazepine immunoassays, PETINIA and EMIT 2000, for in vitro cross-reactivity with HDZ and 2 HDZ metabolites (cetirizine and norchlorcyclizine). To determine the frequency of this interaction in a clinical setting, 40 sera of 39 patients taking HDZ without carbamazepine were tested by both immunoassays. For some samples, LC-ESI-MS analysis of HDZ metabolites was performed. Additionally, cross-reactivities produced by other benzhydrylpiperazine drugs were evaluated. in vitro, 5 mg of HDZ, cetirizine, and norchlorcyclizine cross-reacted with PETINIA at 85%, 125%, and 66%, respectively. Conversely, EMIT 2000 showed no cross-reactivity. For PETINIA, erroneous carbamazepine concentrations were detected in 35 out of 40 sera of patients taking HDZ. The magnitude of interference correlated moderately with serum HDZ concentrations (Spearman rho coefficient 0.58, P < 0.001), suggesting a major role for the multiple HDZ metabolites (4 serum metabolites were detected by LC-ESI-MS). Furthermore, other benzhydrylpiperazine drugs (eg, oxatomide) showed in vitro cross-reactivity with PETINIA. In conclusion, HDZ and its metabolites cross-react with carbamazepine PETINIA immunoassay, which could significantly affect the correct interpretation of serum carbamazepine concentrations in patients treated with HDZ.

False-positive Serum Tricyclic Antidepressant Concentrations Using Fluorescence Polarization Immunoassay Due to the Presence of Hydroxyzine and Cetirizine

“…However, EMIT 2000 assay showed no cross-reactivity. 8 Our results indicate that both FPIA and CEDIA carbamazepine assay are free of clinically significant hydroxyzine and cetirizine interference. Therefore, therapy with hydroxyzine or cetirizine may not affect therapeutic drug monitoring of carbamazepine using FPIA or CEDIA immunoassay.…”

“…12 Cetirizine is the main metabolite of hydroxyzine and its concentrations tend to exceed hydroxyzine concentration. 8 Cetirizine is also used as a second-generation antihistamine agent and a single oral dose of 5 mg in children led to a speak plasma level of 607 ng/mL. 13 Cetirizine overdose has also been reported in a 18-month-old male whose serum cetirizine concentration was 2.4 mg/mL 14 hours after overdose.…”

“…Hydroxyzine hydrochloride was purchased from Sigma Chemical Company and cetirizine was extracted from Zyrtec tablet (cetirizine hydrochloride 10 mg, Pfizer, New York) as described by Parant et al 8 The FPIA assay for both carbamazepine and TCA were obtained from Abbott Laboratories and assays were run on an AxSYM analyzer (Abbott Laboratories, Abbott Park, IL). The CEDIA immunoassay for carbamazepine was obtained from Roche Diagnostics and run on a Hitachi modular P 800 system (Indianapolis, IN).…”

“…8 The fluorescence polarization immunoassay (FPIA) of carbamazepine (Abbott Laboratories) and CEDIA carbamazepine assay marketed by Roche Diagnostics are also widely used for routine measurement of carbamazepine concentrations in serum. According to a recent College of American Pathologists (CAP) survey (ZA series, 2005), 550 out of 3,127 clinical laboratories (that performed carbamazepine immunoassays) used FPIA assay on the AxSYM analyzer, 58 laboratories used assay on the TDx analyzer and 124 laboratories used the CEDIA carbamazepine assay.…”

Analytical performance evaluation of ADVIA Chemistry Carbamazepine_2 assay: minimal cross‐reactivity with carbamazepine 10, 11‐epoxide and none with hydroxyzine or cetirizine

“…The cross-reactivity of carbamazepine 10, 11-epoxide with different immunoassays for carbamazepine may vary between 0 (Vitros) and 94% (Dade Dimension) (6). Hydroxyzine and cetirizine, which are widely prescribed antihistamine drugs, also known to cross-react with the Dade Dimension particle-enhanced turbidimetric inhibition immunoassay (PETINIA) carbamazepine assay (7,8). In this study, we report our findings.…”