Simultaneous determination of ivabradine and N-desmethylivabradine in human plasma and urine using a LC-MS/MS method: application to a pharmacokinetic study

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• 作者：Chengtao Lu^a ; Yanyan Jia^a ; Jing Yang^a ; Xin Jin^a ; Ying Song^a ; Wenxing Liu^a ; Yi Ding^a ; Xiaoli Sun^b ; ^{sunxl_fmmu@163.com} ; Aidong Wen^a ; ^{ad_wen@163.com}
• 关键词：Ivabradine ; N-desmethylivabradine ; Pharmacokinetics ; LC-MS/MS
• 刊名：Acta Pharmaceutica Sinica B
• 出版年：2012
• 出版时间：April, 2012
• 年：2012
• 卷：2
• 期：2
• 页码：205-212
• 全文大小：796 K

文摘

A sensitive and specific liquid-chromatography tandem mass spectrometry (LC-MS/MS) assay has been developed and validated for the simultaneous quantification of ivabradine and its active metabolite N-desmethylivabradine in human plasma and urine. The assay employed a single liquid-liquid extraction of the analytes from plasma and urine samples, and diazepam was used as internal standard (IS). The chromatographic separation was achieved on a Diamonsil C₁₈ column (150 mm¡Á4.6 mm, 5 ¦Ìm, Dikma) using a mixture of methanol and aqueous 5 mM ammonium acetate buffer containing 0.2 % formic acid (80:20, v/v) as mobile phase. The assay for ivabradine and N-desmethylivabradine in plasma showed good linearity (r?.99) over the ranges 0.1013-101.3 ng/mL and 0.085-25.5 ng/mL, respectively. The assay for ivabradine and N-desmethylivabradine in urine showed good linearity (r?.99) over the ranges 10.13-6078 ng/mL and 8.5-850 ng/mL, respectively. The intra- and inter-day accuracy and precision values were found to be within the assay variability limits (RSD<15 % ) in accordance with FDA guidelines. The methods were successfully used for evaluating the pharmacokinetic properties of ivabradine and N-desmethylivabradine in human plasma and urine in Chinese healthy volunteers.