High-Throughput Liquid Chromatography–Tandem Mass Spectrometry Assay for Plasma Theophylline and Its Metabolites

Abstract

3 Department of Laboratory Medicine, Cheju National University College of Medicine, Jeju, Korea; * address correspondence to this author at: Department of Laboratory Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea; fax 82-2-745-6653, e-mail jqkim@plaza. snu.ac.kr)Theophylline is metabolized to 1,3-dimethyluric acid (1,3-DMU), 3-methylxanthine (3MX), and 1-methylxanthine (1MX) mainly by CYP1A2, and 1MX is rapidly converted to 1-methyluric acid (1MU) by xanthine oxidase (1-3 ). Individuals differ in terms of their rates of theophylline metabolism and the resulting serum concentrations (1 ); moreover, some theophylline metabolites, such as 3MX, are known to have bronchodilator activity. Thus, we need to determine the plasma concentrations of theophylline and its metabolites simultaneously to ensure the safe use of theophylline, especially in patients with renal insufficiency, in whom serious side effects can occur if metabolites are allowed to accumulate.Many HPLC methods have been used to measure theophylline and its metabolites. However, most of these techniques require the avoidance of caffeine or require a longer separation time because of the interfering effect of caffeine metabolites such as 1,7-dimethylxanthine (1,7-DMX), 3,7-dimethylxanthine, and theophylline (1,3-dimethylxanthine) (4 ). Recently, liquid chromatographymass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods to determine theophylline and caffeine metabolites have been developed (5, 6 ). However, these methods require two runs per sample, with negative and positive ionization, and the total HPLC run time is ϳ60 min. These methods therefore are not suitable for the high-throughput determinations of theophylline and its metabolites required for routine therapeutic drug monitoring. In the present study, we developed a simple and rapid LC-MS/MS method for the simultaneous determination of plasma theophylline and 2176 Technical Briefs

Analysis of Supramolecular Complexes of 3-Methylxanthine with Field Asymmetric Waveform Ion Mobility Spectrometry Combined with Mass Spectrometry

“…3-MX is a purine derivative and a metabolite of caffeine and theophylline [14,15], and has been monitored biologically in urine and plasma by liquid chromatographic methods [16][17][18][19]. Guanine is a related purine base structure that self-assembles into tetrad structures in biological systems (G-quadruplexes) to form complexes that have been well characterized, theoretically and experimentally [2,[20][21][22][23][24].…”

Effect of decursin on the pharmacokinetics of theophylline and its metabolites in rats

“…In the metabolic pathway of theophylline in rats, it was reported that 30-40% and 15-32% of administered theophylline was metabolized to 1,3-DMU and 1-MX, respectively, and 3-MX was barely detectable (Kizawa et al, 2005;Kokufu et al, 1995;Ha et al, 1995). And 1-MX is immediately transformed into 1-MU by xanthine oxidase (Cornish and Christman, 1957;Jonkman et al, 1981;Song et al, 2004).…”

Analysis of DNA Methylation Status in Bodily Fluids for Early Detection of Cancer

“…On the other hand, several of studies reported fecal DNA methylation for the early detection of CRC or adenoma (Table 3 and Table S3) [54,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74]. In 2004, Müller et al [59] analyzed the hypermethylation of several genes and concluded that hypermethylation of the SFRP2 gene in stool samples can detect CRC with a sensitivity and specificity of 77–90% and 77%, respectively.…”