School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Sep 1;1093-1094:183-189. doi: 10.1016/j.jchromb.2018.05.002. Epub 2018 Jul 20.
Carbinoxamine maleate is an antihistamine drug with mild sedation effects, which is used to treat seasonal and perennial allergic rhinitis clinically. In order to optimize drug therapy, reduce drug accumulation, lessen the frequency of adverse effects and facilitate clinical research, a high performance liquid chromatography tandem mass spectrometry assay was firstly established and fully validated for the quantitative admeasurements of carbinoxamine. After extraction with ethyl acetate, the chromatographic separation was implemented on a C18 column (Hypersil GOLD, 100 mm × 2.1 mm, 3.0 μm) using gradient elution with water (containing 0.1% formic acid) and methanol at the flow rate of 0.4 mL/min. The analytes were measured under multiple reactions monitoring (MRM) mode with m/z 291.2 → 202.1 for carbinoxamine and m/z 285.0 → 193.2 for diazepam (IS) using electrospray ionization source (ESI) in the positive ion mode. A satisfactory linearity was obtained over the wide extent of 0.1-100.0 ng/mL (r > 0.99). Inter- and intra-day precision and accuracy of the assay were favorably accorded with the currently recognized limits (< 8.9%). The mean extraction recoveries for carbinoxamine ranged from 74.00% to 86.4%. The pharmacokinetic characteristics of carbinoxamine were subsequently evaluated in beagles. Following intragastric administration (0.534 mL/kg), carbinoxamine possessed a large apparent volume of distribution of the central compartment (Vc = 1005.7 ± 945.9 L/kg), oral clearance (Cl = 112.446 ± 53.249 L/h/kg), and a relatively long absorption time (T = 2.38 ± 1.00 h). This analytical method with adequate sensitivity was applicable to pharmacokinetic study and could monitor concentrations of carbinoxamine in beagle plasma. Moreover, the methodology could be used for further bioequivalence determination and addressing metabolism associated with the drug.
马来酸卡比沙明是一种具有轻度镇静作用的抗组胺药物，临床上用于治疗季节性和常年性过敏性鼻炎。为了优化药物治疗，减少药物蓄积，减少不良反应的频率，方便临床研究，首次建立并充分验证了高效液相色谱-串联质谱法用于卡比沙明的定量测定。采用乙酸乙酯提取后，以水（含 0.1%甲酸）和甲醇为流动相，在 C18 柱（Hypersil GOLD，100mm×2.1mm，3.0μm）上进行梯度洗脱，流速为 0.4mL/min。采用电喷雾电离源（ESI）在正离子模式下，以 m/z 291.2→202.1 为卡比沙明，m/z 285.0→193.2 为地西泮（IS）进行多反应监测（MRM）模式测定。在 0.1-100.0ng/mL 的宽范围内，得到了令人满意的线性关系（r＞0.99）。该测定方法的日内和日间精密度和准确度均符合目前公认的限度（＜8.9%）。卡比沙明的平均提取回收率在 74.00%至 86.4%之间。随后在比格犬中评价了卡比沙明的药代动力学特征。经胃给药（0.534mL/kg）后，卡比沙明具有较大的中央隔室表观分布容积（Vc=1005.7±945.9L/kg）、口服清除率（Cl=112.446±53.249L/h/kg）和相对较长的吸收时间（T=2.38±1.00h）。该分析方法具有足够的灵敏度，适用于药代动力学研究，并可监测比格犬血浆中卡比沙明的浓度。此外，该方法可用于进一步的生物等效性测定和解决与药物相关的代谢问题。
