Quantitative Analysis of Therapeutic Drugs in Dried Blood Spot Samples by Paper Spray Mass Spectrometry: An Avenue to Therapeutic Drug Monitoring

Abstract

A method is presented for the direct quantitative analysis of therapeutic drugs from dried blood spot samples by mass spectrometry. The method, paper spray mass spectrometry, generates gas phase ions directly from the blood card paper used to store dried blood samples without the need for complex sample preparation and separation; the entire time for preparation and analysis of blood samples is around 30 s. Limits of detection were investigated for a chemically diverse set of some 15 therapeutic drugs; hydrophobic and weakly basic drugs, such as sunitinib, citalopram, and verapamil, were found to be routinely detectable at approximately 1 ng/mL. Samples were prepared by addition of the drug to whole blood. Drug concentrations were measured quantitatively over several orders of magnitude, with accuracies within 10% of the expected value and relative standard deviation (RSD) of around 10% by prespotting an internal standard solution onto the paper prior to application of the blood sample. We have demonstrated that paper spray mass spectrometry can be used to quantitatively measure drug concentrations over the entire therapeutic range for a wide variety of drugs. The high quality analytical data obtained indicate that the technique may be a viable option for therapeutic drug monitoring.

Rapid measurement of tacrolimus in whole blood by paper spray-tandem mass spectrometry (PS-MS/MS)

“…An ionization voltage of +3.4 kV was applied, initiating production of analyte ions from the tip of the paper which were drawn directly into the MS inlet. More information about experimental and fundamental details can be found in the literature (8,9,12). MS conditions were optimized using continuous infusion of tacrolimus and SIL-IS solutions into the commercial H-ESI source by a syringe pump, and SRMs for both compounds selected accordingly (Table 1).…”

“…As the solvent wicks through the sample, soluble components are extracted into the solvent, leaving behind the bulk of proteins and lipids [6]. A high voltage (3-5 kV) is applied to the moist paper, and an electrospray is induced at the sharp tip of the triangular shaped paper in the cartridge, which is held stationary in front of the inlet to the MS. As solvent evaporates, gas phase ions of the analyte molecules are generated which can then be detected by MS. PS-MS/MS has been successfully used for quantitative analysis of xenobiotics (8)(9)(10)) and endogenous compounds (11) from whole blood.…”

Analytical Properties of Solid-substrate Electrospray Ionization Mass Spectrometry

“…Some noncapillary tips such as stainless steel needle [6,19], paper [13,[20][21][22][23], and wooden tips [14] enabled direct analysis of raw samples. Hiraoka and co-workers reported the sequential and exhaustive ionization of analytes on solid metal probe [24].…”

Ionization Suppression and Recovery in Direct Biofluid Analysis Using Paper Spray Mass Spectrometry

“…Paper spray is a member of this growing cohort of ambient ionization or direct analysis methods that was conceived because of the growing interest in storing and transporting blood samples as dried spots. One of the major applications of paper spray mass spectrometry has been screening and quantitative analysis of drugs and other small molecules from biofluids such as blood, urine, and plasma [3][4][5][6][7][8][9][10][11][12][13][14].…”