Fundamental Study of Behaviors of In-Source Collision Induced Dissociation and Shifting the Linear Range of Calibration Curves of Various Drugs and the Metabolites Used for Therapeutic Drug Monitoring

Abstract

Therapeutic drug monitoring (TDM) is a clinical practice that designs personalized medication for patients with blood concentrations of the drug. TDM approach is used for many drugs, including immunosuppressant, antifungal, antiarrhythmic, and anti-cancer drugs. Combination therapies are often adopted in TDM. Liquid chromatography tandem mass spectrometry (LC-MS/MS) is a useful analytical method in such cases. However, the development of a simultaneous LC-MS/MS analytical method is difficult owing to the differences in MS sensitivity and the therapeutic range of each drug. In order to avoid saturation of the detector, in-source collision induced dissociation (CID) was used to reduce the ion inlet. In this study, we investigated the in-source CID behavior of 13 compounds of drugs and metabolites in TDM practice. As a result, all compounds provided a sharp reduction of ion inlet over the threshold ion guide voltage. In addition, a shift to the higher concentration of the calibration range was observed according to such changes. The intensity and linearity data in this study that all 13 drugs could be analyzed under in-source CID conditions simultaneously. These results might be useful for TDM of combination therapy in clinical practice.

Simultaneous analysis of drugs administered to lung‐transplanted patients using liquid chromatography–tandem mass spectrometry for therapeutic drug monitoring

“…The LC–MS/MS conditions were set as previously described (Maekawa et al, 2019. An LCMS‐8050 triple quadrupole mass spectrometer (Shimadzu, Kyoto, Japan) coupled with a Nexera ultra high‐performance liquid chromatograph system (Shimadzu) was used as the LC–MS/MS system.…”

“…The MS conditions were set as follows: probe voltage, 4000 V; interface temperature, 300 C; desolvation line temperature, 250 C; block heater temperature, 400 C; nebulizing gas flow, 3 L/min; drying gas flow, 10 L/min; and heating gas flow, 10 L/min. The selected reaction monitoring conditions for each analyte were optimized as previously described (Table 1, Maekawa et al, 2019).…”

“…To overcome this, a linear range shifting technique using in‐source collision‐induced dissociation (CID) has been developed (Ishii, Shimada, Yamaguchi, & Mano, 2016; Ishii, Yamaguchi, & Mano, 2016; Ishii, Yamaguchi, & Mano, 2017; Takasaki et al, 2018). Basic studies have been conducted on many drugs with different efficacy groups using in‐source CID, and MS conditions have been developed (Maekawa et al, 2019). In this study, we described a simple LC–MS/MS method for simultaneously determining different concentrations of mycophenolic acid, voriconazole, itraconazole, and their metabolites (Figure 1) using previously mentioned MS conditions.…”

“…To overcome this, a linear range shifting technique using in-source collision-induced dissociation (CID) has been developed (Ishii, Shimada, Yamaguchi, & Mano, 2016;Ishii, Yamaguchi, & Mano, 2017;Takasaki et al, 2018). Basic studies have been conducted on many drugs with different efficacy groups using in-source CID, and MS conditions have been developed (Maekawa et al, 2019).…”

Liquid Chromatography

“…4 Maekawa et al reported on in-source collision-induced dissociation and shifting the linear range of calibration curves for therapeutic drug monitoring using UHPLC-MS/MS. 5 Multi-dimensional HPLC is highly effective for the analysis of trace analytes (such as amino acids) in complicated biological samples, as reported by Hamase et al 6 Additionally, HPLC has found applications in other analytical fields, such as analyses of environmental samples 7-10 and foods. [11][12][13][14] The development of new stationary phases is essential to achieve varied and desirable selectivity in HPLC.…”