Therapeutic drug monitoring in dried blood spots using liquid microjunction surface sampling and high resolution mass spectrometry

Abstract

Dried blood spots (DBS) are a versatile and stable tool for direct clinical blood analysis. Ambient high-resolution mass spectrometry is emerging as a method of choice for their quantitative analysis, for instance in therapeutic drug monitoring. Here, we coupled liquid microjunction surface sampling technology, a so-called Flowprobe, with an Orbitrap mass spectrometer and demonstrated the utility of this set-up for direct quantification of multiple drugs in DBS on filter paper. A three-layer set-up that we had introduced earlier enabled introduction of internal standards into DBS. We furthermore took an established point-of-care test system a step further and analyzed disposable test fields for blood glucose monitoring also for Flowprobe-based acetaminophen screening without additional sample preparation. Using as little as 2 μL blood, the method had an LOD of 1 μg mL(-1) (coefficient of variation of ≤15%) and acetaminophen recoveries of 82 to 119% for blinded samples, as assessed by LC-MS/MS. Half an hour after ingestions of a single 1000 mg acetaminophen dose, indistinguishable drug levels were measured in three healthy volunteers by LC-MS/MS and Flowprobe-Orbitrap MS analysis of DBS. Flowprobe analysis of DBS was 6- to 100-times more sensitive than corresponding desorption electrospray ionization MS analysis for four drugs. For instance, the LOD for salicylic acid analysis was 0.07 ng mL(-1) with Flowprobe measurement. Furthermore, we showed that multi-component analysis of five different substances, which may mimic polypharmacy in diabetes patients, in one blood sample for screening purposes was feasible. Taken together, our study suggests that microjunction surface sampling of DBS on filter paper and disposable point-of-care test fields may be developed into routine methods for near-patient multi-compound therapeutic drug monitoring that may advance blood screening analysis for patients with polypharmacy.

Emerging trends in paper spray mass spectrometry: Microsampling, storage, direct analysis, and applications

“…Sealing surface‐sampling probe mass spectrometry (SSSP‐MS) and liquid microjunction surface‐sampling probe mass spectrometry (LMJ‐SSP‐MS) are employed as unilateral extraction techniques. LMJ‐SSP‐MS and SSSP‐MS allow for the extraction of soluble materials (e.g., small molecules such as dyes, drugs, natural products (Gaissmaier et al, ), and larger molecules such as peptides and proteins) on surfaces (e.g., thin layer chromatography plates, thin tissue sections, spotted sample arrays, affinity arrays, stainless steel, glass, glassy carbon, hydrophobic paper, etc.) coupled to direct analysis by MS (Van Berkel & Kertesz, ).…”

“…LMJ‐SSP‐MS is useful for therapeutic drug monitoring in DBSs, which (i) minimizes additional sample preparation, (ii) allows for very small sample volumes (2 µL), and (iii) has enhanced sensitivity compared to other direct analysis techniques such as DESI‐MS. The enhanced sensitivity is attributed to the direct ESI processes (Gaissmaier et al, ).…”

Direct sampling mass spectrometry for clinical analysis

“…Gaissmaier et al reported using a commercialized version of LMJ-SSP, Flowprobe (Prosolia), for TDM with DBS samples. 100 The LOQ for acetaminophen was determined to be 5 μg/mL, although the sensitivity of method was limited, it was still appropriate for acetaminophen (10-20 μg/mL), covering the entire therapeutic range. LMJ-SSP was also coupled with online photochemical Paternò-Büchi reaction to perform rapid in situ determination of lipid C=C location isomers in tissue samples (Fig.…”

Fast direct detection of natural dyes in historic and prehistoric textiles by flowprobe™-ESI-HRMS

“…Interestingly, the use of direct MS methods including in situ extractions, for example DESI (desorption electrospray ionization)-and LMJ-SSP (liquid microjunction surface sampling probe)-MS, for dyestuff analyses of ancient textiles was until now not reported, although these methods were successfully applied in biochemical and forensic research. [24][25][26][27][28][29][30][31] In this study, we present the rst rapid and minimally invasive dyestuff analysis under ambient conditions through real-time in situ microextractions of bers by owprobe™-ESI-HRMS (high-resolution MS), a commercial LMJ-SSP device coupled with an Orbitrap mass analyzer. This system uses a pair of coaxial capillaries (probe outer diameter ¼ 630 mm) being positioned close to the surface of the examined object.…”