title: Simultaneous determination of erlotinib and tamoxifen in rat plasma using UPLC-MS/MS: Application to pharmacokinetic interaction studies.
abstract: Tamoxifen (TAM) is a non-steroidal estrogen receptor antagonist that enhances erlotinib (ERL)-induced cytotoxicity 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 induction (TAM). Thus it was expected that pharmacokinetics (PK) drug-drug interactions (DDIs) could be encountered following their co-administration. In this respect, a bioanalytical UPLC-MS/MS method has been 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 mode cationic solid phase extraction (SPE) STRATA™ -X-C 33μm cartridges with good extraction recovery of both drugs from rat plasma (Er% from -13.92 to -3.32). The drugs were separated on a Waters BEH™ C18 column 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 ionization 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 over the concentration range of 0.2-50ng/mL with very low lower limit of quantification (LLOQ) of 0.2ng/mL for 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 calculated 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 study of possible PK-DDI following the oral administration of ERL and TAM in a combination, compared to their single administration.
authors.affiliation: College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia; Faculty of Pharmacy, Department of Pharmaceutical Analytical Chemistry, University of Alexandria, El-Messalah, Alexandria 21521, Egypt. Electronic address: hadirrona@yahoo.com.
authors.forename: Hadir M
authors.initials: HM
authors.lastname: Maher
authors.affiliation: College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia.
authors.forename: Nourah Z
authors.initials: NZ
authors.lastname: Alzoman
authors.affiliation: College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia.
authors.forename: Shereen M
authors.initials: SM
authors.lastname: Shehata
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D016903:Drug Monitoring / Q000379:methods; D000069347:Erlotinib Hydrochloride / Q000097:blood*; D004965:Estrogen Antagonists / Q000097:blood*; D057230:Limit of Detection; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D052616:Solid Phase Extraction / Q000379:methods; D013629:Tamoxifen / Q000097:blood*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D013629:Tamoxifen; D000069347:Erlotinib Hydrochloride
keywords: Erlotinib; Pharmacokinetics; Rat plasma; SPE; Tamoxifen; UPLC–MS/MS