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Journal of Analytical Toxicology 2015;39:75–79 doi:10.1093/jat/bku120 Advance Access publication October 16, 2014 Case Report

Multidrug Toxicity Involving

Jessica L. Knittel*, Shawn P. Vorce, Barry Levine, Rhome L. Hughes and Thomas Z. Bosy Division of Forensic Toxicology, Armed Forces Medical Examiner System, Dover AFB, Dover, DE 19902, USA

*Author to whom correspondence should be addressed. Email: [email protected]

A multidrug fatality involving sumatriptan is reported. Sumatriptan is warmth or cold, dizziness, numbness, , tingling, , a derivative that acts at 5-HT1B/1D receptors and is used heaviness and chest, neck or throat tightness (1–3). However, for the treatment of . The decedent was a 21-year-old white more serious cardiovascular complications such as coronary va- female found dead in bed by her spouse. No signs of physical trauma sospasm, , ischemic colitis, were observed and a large number of prescription were and have occurred in some patients (1). Downloaded from https://academic.oup.com/jat/article/39/1/75/2798061 by guest on 29 September 2021 discovered at the scene. Toxicological analysis of the central blood The adverse effects most commonly occur with subcutaneous revealed sumatriptan at a concentration of 1.03 mg/L. Following ther- administration but have also been observed after single oral and apeutic dosing guidelines, sumatriptan concentrations do not exceed intranasal doses (7, 8). As the dose of any formulation of suma- 0.095 mg/L. Sumatriptan was isolated by solid-phase extraction and increases, the risk of an adverse event occurring also in- analyzed using liquid chromatography–tandem mass spectrometry in creases. Sumatriptan is not recommended for individuals with a multiple reaction monitoring mode. A tissue distribution study was history of heart disease, other significant vessel disease, uncon- completed with the following concentrations measured: 0.61 mg/L trolled hypertension or recent use of ergot-type or monoamine in femoral blood, 0.56 mg/L in iliac blood, 5.01 mg/Linurine, oxidase inhibiting medications. However, a number of case re- 0.51 mg/kg in liver, 3.66 mg/kg in kidney, 0.09 mg/kg in heart, ports described in the medical literature have revealed that pa- 0.32 mg/kg in spleen, 0.01 mg/kg in brain, 15.99 mg/kg in lung tients with no underlying cardiac conditions can suffer from and 78.54 mg/45 mL in the stomach contents. Carisoprodol, mepro- cardiac events when using sumatriptan (7–13). bamate, fluoxetine, doxylamine, orphenadrine, dextromethorphan The following case report presents the development of a solid- and were also present in the blood at the following con- phase extraction and a quantitative liquid chromatography– centrations: 3.35, 2.36, 0.63, 0.19, 0.06, 0.55 and 0.16 mg/L. The tandem mass spectrometry (LC–MS-MS) method for sumatriptan medical examiner ruled the cause of death as acute mixed drug tox- in biological specimens. This method was then applied to a post- icity and the manner of death as accident. mortem case where sumatriptan was identified as a contributing factor in the death of an individual.

Introduction Case report Sumatriptan (3-(2-[dimethylamino]ethyl)-N-methyl-indole- A 21-year-old Caucasian female was found unresponsive in bed by 5-mathanesulfonamide) (Figure 1) is a used her spouse. CPR was started but by the time emergency medical in the treatment of migraines and cluster . Available services arrived rigor mortis had begun and the victim was pro- in the USA since 1993, this tryptamine derivative is currently nounced dead. The spouse reported that the decedent had a history available as a subcutaneous (Imitrexw, Alsumaw, of epilepsy, asthma and chronic residual subsequent to scolio- Sumavelw), (Imitrexw, Imigranw and an ingredient in sis surgical repair. The decedent had not been feeling well the day Treximetw), (Imitrexw) and more recently as a transder- before and had sought medical attention. At the hospital, she re- mal patch (Zelrixw/Zecuityw). The parenteral, tablet and transder- ceived treatment, prescriptions for carisoprodol and carbamaze- mal formulations are manufactured as the succinate salt; while pine, and was sent home. The spouse stated that she had been the nasal spray is produced as the free base. All formulations of breathing when he went to bed at 02:30 a.m. An initial investigation sumatriptan are quickly absorbed and widely distributed into of the scene revealed a large number of prescription medications. body tissues. The therapeutic plasma drug concentrations for During the autopsy, the decedent displayed no external inju- sumatriptan range from 0.013 to 0.095 mg/L with an elimination ries though small amounts of vomit were found in the trachea half-life of 1–4 h (1). Daily doses in adults should not exceed and primary bronchi. Both lungs displayed moderate congestion 40 mg intranasally, 12 mg parenterally, 300 mg orally (1)or and edema, with the right lung weighing 610 g and the left lung 13 mg transdermally (two patches). 630 g. The coronary arteries appeared to be normal with ,10% Sumatriptan is a selective (5-HT) , which acts luminal obstruction in the left anterior descending artery. The at the 5-HT1B/1D receptors causing and inhibit- gastrointestinal contents contained undigested food particles. ing vasoactive from being released by the trigem- All other findings were unremarkable. Postmortem specimens inal nerves. The constriction of the cerebral blood vessels is were submitted for a comprehensive toxicological examination mediated by the 5-HT1B receptors, which are found primarily to include volatiles, drugs of abuse and therapeutic medications. on the meningeal arteries (2, 3); however, 5-HT1B receptors are also found on pulmonary, coronary and other peripheral arteries Experimental (4–6). This widespread distribution of 5-HT1B receptors may help explain the diversity in the adverse effects that are occasion- Chemicals and materials ally observed with sumatriptan use. Adverse effects of sumatrip- All solvents were of high-performance liquid chromatography tan typically consist of transient drowsiness, sedation, feelings of (HPLC) grade or better and were purchased from Fisher

# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] columns previously conditioned with 3 mL of methanol, 3 mL of deionized water and 3 mL of 0.1 M phosphate buffer (pH 6.0). The samples were allowed to flow through the columns by gravity followed by sequential washes with 2 mL of deionized water, 2 mL of 20% acetonitrile in deionized water and 1 mL of 0.1 M acetic acid. The columns were dried for 2 min, followed by two additional washes the first consisting of 2 mL of hexane and the second, 3 mL of methanol. The columns were dried under vacuum for 10 min. Samples were eluted with 3 mL of dichloromethane/isopropanol/ammonium hydroxide (78:20:2), and the eluents evaporated at 258C under nitrogen. The dried samples were reconstituted with 50 mL of acetonitrile, vortexed and transferred to autosampler vials.

Specimens were analyzed by gas chromatography mass spec- Downloaded from https://academic.oup.com/jat/article/39/1/75/2798061 by guest on 29 September 2021 trometry (GC/MS) using an Agilent (Palo Alto, CA) 6890 GC cou- pled to a 5975 mass selective detector (MS). The GC column was a J&W DB-5MS (20 m  0.18 mm i.d. 0.18 mm, Rancho Cordova, CA) with helium as the carrier gas maintained at a constant flow of 1.0 mL/min. Two microliters of sample were injected using a Figure 1. Structure of sumatriptan. 10:1 split, an inlet temperature of 2508C and a 4-mm inlet liner packed with deactivated glass wool. An initial oven temperature of 708C was held for 1 min, increased at a rate of 188C/min to Scientific (Pittsburgh, PA). Hydrochloric acid and formic acid 3008C and held for 10 min, for a total run time of 23.78 min. were also acquired from Fisher Scientific. Ammonium formate, The MS source and quadrapole temperatures were 230 and sodium phosphate monobasic, sodium phosphate dibasic and 1508C, respectively, with the transfer line set at 2808C. acetic acid were purchased from Sigma-Aldrich Chemicals Full-scan electron ionization MS data were collected over a (St Louis, MO). Sumatriptan succinate was also acquired mass range from m/z 42 to 550 with an acquisition threshold from Sigma-Aldrich Chemicals. A second source of sumatriptan of 150 counts. was purchased from US Pharmacopeial (USP, Rockville, MD). Sumatriptan-d6 was purchased from Santa Cruz Biotechnology (Dallas, TX). Mixed mode silica based solid-phase extraction col- Quantitative analysis umns (ZCDAU020) were acquired from United Chemical To 1 mL of samples, calibrators and controls, 50 mLofsumatriptan- Technologies (UCT, Bristol, PA). d6 working internal standard solution was added for a final concentration of 0.050 mg/L. Following the addition of 2 mL Standards, calibrators and control preparation of 0.1 M phosphate buffer (pH 6.0), the samples were vortexed, sonicated for 10 min and centrifuged at 3,000 rpm for 10 min. Stock solutions of both sumatriptan standards were prepared at a Solid-phase extraction columns were conditioned successively target concentration of 1,000 mg/L in methanol and stored at with 2 mL of methanol, 2 mL of deionized water and 2 mL 2208C. An internal standard stock solution of sumatriptan-d 6 of 0.1 M phosphate buffer (pH 6.0). The samples were applied was prepared at a concentration of 1,000 mg/Linmethanol to the conditioned columns and allowed to flow through by and stored at 2208C. Calibrator and control working solutions gravity. When the application was complete, the columns were from separate sumatriptan sources were prepared by serial dilu- washed sequentially with 2 mL of deionized water, 2 mL tion with methanol at concentrations of 10, 1.0 and 0.10 mg/L. of 0.1 M acetic acid, 2 mL of methanol and dried under vacuum The internal standard working solution was prepared at a con- for 10 min. Compounds were eluted from the columns centration of 1.0 mg/L. using 3 mL of dichloromethane/isopropanol/ammonium hy- Sumatriptan calibrators were prepared in 1.0 mL of certified droxide (78:20:2). Ten microliters of 10% hydrochloric acid in drug-free negative blood at concentrations of 0.001, 0.005, methanol were added to the eluents, which were vortexed and 0.010, 0.025, 0.050, 0.100, 0.250 and 0.500 mg/L. Positive con- evaporated at 408C under nitrogen. In preparation for LC–MS-MS trols were prepared daily from the control working solutions at analysis, the dried samples were reconstituted in 50 mL of mobile concentrations of 0.005, 0.075 and 0.300 mg/L. Calibrators, pos- phase (80:20 0.1% formic acid in deionized water/20% acetoni- itive controls and a negative control were analyzed with each trile in methanol), vortexed and transferred to labeled autosam- batch of samples. pler vials. LC–MS-MS analysis was performed using a Waters Acquity Qualitative analysis Ultra Performance liquid chromatograph (UPLC) coupled to a To prepare the samples for extraction, 3 mL of 0.1 M phosphate Xevo tandem quadrapole detector (TQD) equipped with an elec- buffer (pH 6.0) were added to the urine specimens (2 mL). A trospray ionization (ESI) source (Waters, Milford, MA). Masslynx 10 mg/L working internal standard solution containing mepiva- and Targetlynx software were used for data acquisition and anal- caine and ethylmorphine was added for a final internal standard ysis, respectively. concentration of 0.500 mg/L. The samples were centrifuged for Chromatographic separation was performed on a Waters 15 min at 3,000 rpm and applied to the solid-phase extraction Acquity UPLC HSS T3 column (2.1  50 mm, 1.8 mm). The

76 Knittel et al. column compartment was maintained at 358C and the injection Table I volume was set at 3 mL. A gradient elution was performed with Compound-Dependent Parameters 10 mM ammonium formate (mobile phase A) and 20% acetoni- Compound MRM transition Cone voltage (V) Collision energy (eV) trile in methanol with 0.1% formic acid (mobile phase B) at a constant flow rate of 0.35 mL/min. Gradient conditions were as Sumatriptan-d6 302.2/157.0 40 32 302.2/251.0 40 18 follows: initial conditions of 15% B increased to 40% B over Sumatriptan 296.1/157.0 38 30 2.50 min, ramped to 80% B at 2.75 min and held for 0.5 min, 296.1/251.0 38 20 ramped to 15% B at 3.5 min and re-equilibrated at 15% B for 2.00 min, for a total run time of 5.5 min. The MS was operated in positive ESI mode with analysis oper- Table II ated in multiple reaction monitoring (MRM) acquisition mode. Method Validation Data for Sumatriptan in Blood Two MRM transitions were monitored for both sumatriptan Linearity (n ¼ 12) 0.001–0.500 mg/L and internal standard. Source-dependent parameters were opti- r2 .0.99723 mized by injecting an unextracted 0.500 mg/L sample multiple LOD (mg/L) 0.00005 Downloaded from https://academic.oup.com/jat/article/39/1/75/2798061 by guest on 29 September 2021 LOQ (mg/L) 0.00025 times and varying different source parameters with each injec- ULOL (mg/L) 1.0 tion. The optimized source-dependent parameters were as fol- Precision SDa CVb lows: desolvation temperature, 4508C; desolvation gas flow, Within-day (n ¼ 5) 850 L/h; cone gas flow, 20 L/h; source temperature, 1508C; Low control 0.07 1.6% Mid control 1.85 2.5% cone voltage, 25 V; capillary voltage, 3.5 kV and extractor voltage, High control 4.07 1.5% 3.0 V. Between-day (n ¼ 12) The compound-dependent parameters for the MS-MS were de- Low control 0.19 4.2% Mid control 2.99 4.1% termined using a combined mobile phase and standard infusion. High control 3.86 1.4% The infusion pump delivered both the 1.00 mg/L standard solu- Accuracy % diff tion and mobile phase at initial conditions at a constant flow Within-day (n ¼ 5) (10 mL/min) directly into the source. The Optimizer auto- Low control 28.9% Mid control 20.5% optimization program determined the optimal cone voltage High control 1.5% and collision energy for each MRM transition. Table I lists the Between-day (n ¼ 12) compound-dependent parameters and MRM transitions moni- Low control 29.8% Mid control 23.0% tored for sumatriptan and internal standard. High control 28.2%

aStandard deviation. Method validation bDefined as the [(standard deviation/mean) Â 100]. The following parameters were measured for the validation of sumatriptan: selectivity, specificity, linearity, limit of quantitation extraction. Matrix effect was determined by comparing a sample (LOQ), limit of detection (LOD), upper limit of linearity (ULOL), spiked post-extraction to an unextracted sample. Ion suppres- within- and between-day precision, accuracy, carryover, extrac- sion was noted if the difference in response was negative and tion recovery and matrix effects. ion enhancement if the response was positive. The linear relationship was evaluated by calculating the line of regression of the eight point curve(s) using the least squares method. The minimum coefficient of determination (R2) of the Results and Discussion calibration curve must be 0.980 or better. Additionally, each cal- Method validation ibrator was back calculated against the generated curve and com- The validation data met all acceptable criteria for method valida- pared with the theoretical concentrations. The LOD was defined tion. Endogenous components and commonly encountered/ as the lowest concentration for which the MRM transition ratios structurally related compounds did not produce any interference are within +20% of the average MRM transition ratio and +3% or quantitative issues for the LC–MS-MS analysis of sumatriptan. of the relative retention time but had no defined relationship to Using 1/x weighting, the assay was determined to be linear from the theoretical spiked concentration. The LOQ and ULOL were 0.001 to 0.500 mg/L. No significant ion suppression or enhance- defined as the lowest and highest concentration, respectively, ment was detected. Recovery values ranged between 55 and 66% that meet all the above criteria and were within +20% of the for both sumatriptan and sumatriptan-d but were determined to theoretical spiked concentration. 6 be sufficient at all concentrations of the calibration curve includ- The acceptable values of precision, expressed as the coeffi- ing the LOQ. The validation data including linearity, LOD, LOQ, cient of variance (CV), for each within- and between-day assay ULOL, precision and accuracy are displayed in Table II. must be 15%. Accuracy, defined as the percent difference (% diff) between the average calculated concentration and the the- oretical spiked concentration, was also evaluated during each ex- Case results traction. Each control must be within +20% of the theoretical Postmortem specimens were screened for volatile substances, spiked concentration to be considered acceptable. therapeutic drugs and drugs of abuse. No ethanol or other Recovery, defined as the amount of analyte lost during the ex- volatile compounds were detected in either the blood or the traction procedure, was calculated by comparing a sample with vitreous humor at the cutoff level of 0.02 g/dL. Immunoassay standard spiked pre-extraction to a sample spiked post- was used to screen the urine for , barbiturates,

Multidrug Toxicity Involving Sumatriptan 77 benzodiazepines, benzoylecgonine, cannabinoids, MDMA, opi- First, the two peripheral blood specimens have sumatriptan con- ates, oxycodone, phencyclidine and 6-acetylmorphine. The centrations 40% lower than the central blood concentration. urine screened positive for opiates with the presence of hydro- Cardiac to peripheral blood ratios (C/P) were 1.68 for the femo- morphone being confirmed in the urine by GC–MS. No hydro- ral blood and 1.83 for the iliac blood. C/P ratios and volumes of morphone was detected in the blood at a concentration distribution for 113 drugs were published by Dalhe-Scott et al. .0.05 mg/L. (15). The C/P ratios and volume of distribution for sumatriptan Based on the prescription history of the decedent, compre- are comparable to the values reported for amantadine, clonaze- hensive full-scan acid/neutral and alkaline drug screens were pam, orphenadrine, thiopental and all of which may po- performed on the urine specimen using GC/MS. Meprobamate tentially exhibit postmortem redistribution (1, 15). Second, the was identified in the acid/neutral drug screen. Using GC/MS, lung concentration is an order of magnitude higher than the both meprobamate and carisoprodol were confirmed and quan- blood or liver sumatriptan concentrations. The high concentra- titated in the blood. The alkaline screen identified fluoxetine, tion of sumatriptan in the lung may be due in part to the pres- doxylamine, orphenadrine, dextromethorphan and hydroxyzine. ence of vomit found in the decedent’s trachea and primary

The presence of each of these drugs was confirmed in the urine bronchi during autopsy. Vomit in the airways has been associated Downloaded from https://academic.oup.com/jat/article/39/1/75/2798061 by guest on 29 September 2021 and quantitated in the blood. The quantitative blood results for with postmortem redistribution and specifically an increase in each of the compounds mentioned above are displayed in cardiac blood concentrations (16, 17). Moreover, when the Table III. Additionally, nicotine, cotinine, trimethoprim and me- drug concentration in the heart blood is greater than that of tabolites or breakdown products of hydroxyzine, dextromethor- the myocardium, it has been suggested that redistribution from phan, gabapentin and were detected in the urine the lungs has occurred (17). The C/P blood ratios and the pres- but not quantitated. Sumatriptan was also identified by the alka- ence of vomit in the lungs indicate that postmortem redistribu- line screen and quantitated in the central blood at a concentra- tion of sumatriptan has likely occurred. However, additional case tion of 1.03 mg/L. Given that the concentration of sumatriptan reports are required before a more definite statement about post- identified in the decedent’s blood was approximately ten times mortem redistribution can be made. greater than concentrations reported in the literature for thera- Another area of interest centers around why the liver drug peutic use, a tissue distribution study was performed on all sub- concentration is lower than both the central and peripheral mitted postmortem specimens. Blood calibrators were used to blood concentrations. The liver to central blood concentration quantitate the tissue specimens after preparing tissue homoge- ratio is 0.49; while the liver to femoral and iliac blood ratios are nates in water. Tissues were diluted to ensure quantitation with- 0.83 and 0.91, respectively. Several cases involving tryptamine in the limits of the standard curve. The tissue distribution results overdoses have examined liver to blood concentration ratios. In are displayed in Table IV. a single overdose case, Sklerov et al. (18) observed a liver to heart Review of the sumatriptan concentrations measured in the blood 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) con- blood and tissue specimens identifies several areas of interest. centration ratio of 8.7 and liver to peripheral blood concentra- tion ratio of 13.6. Additionally, Boland et al. (19)reporteda fatality due to a-methyltryptamine (AMT) with liver to peripher- Table III al blood concentration ratio of 12.3. Finally, Morano et al. (20) Quantitative Results in Blood (14) observed a liver to heart blood ratio of 3.2 in a single ethyltrypt- Drug Blood source Concentration (mg/L) amine overdose case. Based on the autopsy and analytical findings in this case, the Sumatriptana Central 1.03 .Therapeutic Carisoprodol Central 3.35 ,Therapeutic medical examiner ruled the cause of death was acute mixed Meprobamate Central 2.36 ,Therapeutic drug toxicity and the manner of death was accidental. While Femoral 0.63 Subtoxic Doxylamine Femoral 0.19 Therapeutic toxic and lethal concentration ranges have not yet been estab- Orphenadrine Femoral 0.06 ,Therapeutic lished for sumatriptan, the quantitative results measured in this Dextromethorphan Femoral 0.55 Toxic case were deemed significant to the death as they were consider- Hydroxyzine Central 0.16 Toxic Hydromorphone Central None detected ably higher than the reported therapeutic concentrations. However, the death cannot be entirely attributed to sumatriptan. aToxic and lethal ranges have not been established. Dextromethorphan and hydroxyzine were identified at toxic but not fatal levels; while the remaining drugs were identified at ther- apeutic or subtherapeutic levels. Individually, these drugs may not Table IV have caused the fatality but synergistic effects may have occurred, Distribution of Sumatriptan in Postmortem Specimens so they cannot be ignored when determining the cause of death. Source Concentration (mg/Lormg/kg) Central blood 1.03 Femoral blood 0.61 Funding Iliac blood 0.56 This work was funded in part by the American Registry of Urine 5.01 Liver 0.51 Pathology, Camden, Delaware 19934. Kidney 3.66 Heart 0.09 Spleen 0.32 Conflict of interest Brain 0.01 Lung 15.99 The opinions or assertions presented hereafter are the private Gastric 78.54 mg (45 mL submitted) views of the authors and should not be construed as official or

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Multidrug Toxicity Involving Sumatriptan 79