Simultaneous determination of erlotinib and tamoxifen in rat plasma using UPLC-MS/MS: application to pharmacokinetic interaction studies
Shehata, Hadir M. Maher, Nourah Z. Alzoman, Shereen M. . 2016
Tamoxifen (TAM) is a non-steroidal estrogen receptor antagonist that enhances erlotinib (ERL)-inducedcytotoxicity in the treatment of NSCLC. ERL and TAM are metabolized by CYP3A4 enzymes. In addition,both drugs have the potential of altering the enzymatic activity through either inhibition (ERL) or induc-tion (TAM). Thus it was expected that pharmacokinetics (PK) drug–drug interactions (DDIs) could beencountered following their co-administration. In this respect, a bioanalytical UPLC–MS/MS method hasbeen developed and validated for the simultaneous determination of ERL and TAM in rat plasma samples,using ondansetron (OND) as an internal standard (IS). Plasma samples were prepared using mixed modecationic solid phase extraction (SPE) STRATATM−X-C 33 m cartridges with good extraction recovery ofboth drugs from rat plasma (Er% from −13.92 to −3.32). The drugs were separated on a Waters BEHTMC18column with an isocratic elution using a mobile phase composed of a mixture of acetonitrile and water,each with 0.15% formic acid, in the ratio of 80: 20, v/v. Quantitation was carried out using the positive ion-ization mode with multiple reaction monitoring (MRM) at m/z 394.20 > 278.04 (ERL), m/z 372.25 > 72.01(TAM), and m/z 294.18 > 170.16 (OND). The method was fully validated as per the FDA guidelines overthe concentration range of 0.2–50 ng/mL with very low lower limit of quantification (LLOQ) of 0.2 ng/mLfor both ERL and TAM. The intra- and inter-day assay precision (in terms of relative standard deviation,RSD) and accuracy (in terms of percentage relative error, % Er) were evaluated for both drugs and the cal-culated values evaluated at four different concentration levels were within the acceptable limits (<15%)for concentrations other than LLOQ and 20% for LLOQ. The method was successfully applied to the studyof possible PK-DDI following the oral administration of ERL and TAM in a combination, compared to theirsingle administration.
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