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The Postmortem Distribution of Vardenafil (Levitra | in an Aviation

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The Postmortem Distribution of Vardenafil (Levitra | in an Aviation Journal of Analytical Toxicology, Vol. 31, July/August 2007 The Postmortem Distribution of Vardenafil (Levitra| in an Aviation Accident Victim with an Unusually High Blood Concentration* Robert D. Johnson ~, Russell J. Lewis, and Mike K. Angler Downloaded from https://academic.oup.com/jat/article/31/6/328/682815 by guest on 27 September 2021 Civil Aerospace Medical Institute, Federal Aviation Administration, Analytical Toxicology and Accident Research Laboratory, AAM-610, CAMI Building, 6500 S. MacArthur Blvd., Oklahoma City, Oklahoma 73169-6901 I Abstract phodiesterase type 5 enzyme (PDE5) found predominantly in the penile corpus cavernosum (2-7). Vardenafil (tevitra) is one of the most widely prescribed Vardenafil undergoes hepatic metabolism, producing the treatments for erectile dysfunction. This report presents a active desethyl metabolite M1. M1 contributes to the ob- rapid and reliable method for the identification and quantification served pharmacological effects provided by vardenafil, as M1 of vardenafil in postmortem fluids and tissues, applies this method exhibits approximately 30% of the potency of the parent to a postmortem case, and describes the distribution of vardenafil in various fluids and tissues.This procedure utilizes sildenafil-d8, drug (1). Under steady-state conditions, the plasma concen- which is structurally closely related to vardenafil, as an tration of M1 is approximately 26% of that seen for vardenafil internal standard for more accurate and reliable quantitation. (1). After oral administration of vardenafil, peak plasma con- The method incorporates solid-phaseextraction and liquid centrations are obtained within 30-60 min (1). Vardenafil chromatography-tandem mass spectrometry (MS) and and its active metabolite have a terminal half-life of approx- MS-MS-MS utilizing an atmospheric pressure chemical imately 4-5 h (1). ionization ion trap MS in the positive chemical ionization mode. Vardenafi], though relatively safe, has certain side effects Solid-phase extraction proved to be exceptionally efficient that could create aviation safety-related hazards. Like its struc- providing recoveries that ranged from 94% to 97%. The limit tural relative sildenafil, vardenafil inhibits PDE5, and it also has of detection for vardenafil was determined to be 0.19 ng/mL. a high affinity for phosphodiesterase type 6 (PDE6), a retinal The linear dynamic range for this compound was 0.39-200 ng/mL. enzyme involved in phototransduction (1,8). The inhibition This method was successfullyapplied to postmortem fluid and tissue specimens obtained from an aviation accident victim. of PDE6 can result in a condition known as "blue tinge", the in- The distribution of vardenafil in various fluids and tissuesand ability to discriminate between blue and green colors (9). This the unusually high concentration of vardenafil in the victim's "blue tinge" impairment could hinder a pilot relying upon in- blood are examined. struments during adverse meteorological conditions and/or night flights (10). Additionally, vardenafil has been shown to potentiate the hypotensive effects of nitrates commonly em- ployed in the treatment of certain heart conditions (11). Introduction Other work that utilizes liquid chromatography-electro- spray ionization mass spectrometry (LC-ESI-MS) for the iden- Vardenafil (Levitra), prescribed as an oral treatment for erec- tification of vardenafil has been published (12,13). However, the tile dysfunction (ED), was introduced in the United States in authors did not find any atmospheric pressure chemical ion- 2003. Within a year of its introduction, vardenafil prescriptions ization (APCI) methods referenced or any other analytical work increased approximately 400%, and it is now one of the most done in postmortem specimens. Because of its increasing pop- widely prescribed treatments for ED (1). Vardenafil, 1-{[3-(1,4- ularity, the presence of vardenafil in aviation accident victims dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin- will become more common. This paper describes one such 2-yl)-4-ethoxyphenyl]sulfonyl/-4-ethyl-piperazine, shown in aviation accident victim. In this case, high concentrations of Figure 1, is a selective inhibitor of the cGMP-specific phos- vardenafil were found in various tissues and fluids obtained from the victim. Solid-phase extraction (SPE) and LC with * This research is part of an Office of Aerospace Medicine Research Report. APCI ion trap (IT) MS were used to quantify vardenafil in each ~ Aulhor to whom correspondence should be addressed. E-mail: r specimen examined. 328 Reproduction(photocopying) of editorial contentof this journal is prohibitedwithout publisher'spermission. Journal of Analytical Toxicology, Vol. 31, July/August 2007 stored in 50:50, acetonitrile/H20. Initially, A B precursor ions were identified for both o 0 D D\ ID compounds. Following [M+H]§ ion iden- tification, ionization conditions were op- N. II I \\ ~N~ /~--D timized by infusing each analyte directly into the mobile phase, which was then introduced into the MS at a flow rate of ) ) 1.00 mL/min. Tuning the MS for the de- sired ions was then accomplished using Vardenafil Sildenafil-d8 the autotune feature of the Xcalibur TM software. Each sample analysis consisted Figure 1. Chemical structures of vardenafil (A)and si Idenafil-d 8 (B). of one data collection segment. This seg- ment collected data for both vardenafil and the internal standard sildenafil-ds. Downloaded from https://academic.oup.com/jat/article/31/6/328/682815 by guest on 27 September 2021 Materials and Methods The operating conditions for the data collection segment were as follows: APCI capillary temperature, 175~ APCI va- Chemicals and solutions porizer temperature, 450~ source voltage, 4.00 kV; source All aqueous solutions were prepared using double deion- current, 4.00 pA; sheath gas flow (nitrogen), 80.0; auxiliary gas ized water (DDW), which was obtained using a Milli-QTplus flow (nitrogen), 20.0; capillary voltage, 23.0 V; tube lens offset, Ultra-Pure Reagent Water System (Millipore| Continental 35.0 V; octapole I offset, -1.75 V; octapole 2 offset, -6.00 V; in- Water Systems, El Paso, TX). All chemicals were purchased in teroctapole lens voltage,-18.00 V; trap DC offset voltage,-15 the highest possible purity and used without any further pu- V; multiplier voltage, 0.0 V; and 1 microscan having a max- rification. All solvents were of HPLC-grade and were obtained imum ion injection time of 100 ms. This segment was further from Fisher Scientific (Fischer Scientific, Fair Lawn, NJ). split into three separate scan events. Scan event 1 collected the Formic acid (97%) was purchased from ICN Biomedicais sildenafil-d8 and vardenafil precursor, [M+H]§ ions at m/z (Irvine, CA). Vardenafil was obtained from Bayer Pharmaceu- 483.3 and m/z 489.4, respectively. Scan event 2 collected the tical Corporation (West Haven, CT). Sildenafil-d8was synthe- vardenafil product ions at m/z 376.0 and 376.1 following col- sized by and obtained from SynFine Research (Richmond Hill, lision-induced dissociation (CID) of the precursor ion (m/z ON, Canada). 489.4) using a collision energy of 46%. Scan event 3 collected Stock standard solutions of vardenafil were prepared at a the vardenafil MS3 product ion at m/z 284.1 following CID of concentration of 1 mg/mL in methanol. A stock solution of the the MS-MS product ion (m/z 376.0) using a collision energy internal standard, sildenafil-ds, was prepared at 100 ~g/mL in of 42%. methanol. Formic acid (50raM) constituted the aqueous por- Ions having the highest abundance in the MS-MS mode tion of the high-performance liquid chromatography (HPLC) were used for quantitation of vardenafil. The MS-MS spectra mobile phase and was adjusted to pH 5.00 with concentrated of vardenafil provided two predominant ions. These ions, at ammonium hydroxide. The formic acid buffer was mixed with m/z 376.0 and m/z 377.1, were summed for the quantitation acetonitrile in a 98:2 (v/v) ratio to help prevent the growth of of this compound. The molecular ion of the internal stan- microbes. This mixture was filtered through a vacuum fil- dard, sildenafil-ds, at m/z 483.3 was utilized for quantitation. tering apparatus that incorporated a 0.45-~m GH polypro 47- The MS-MS-MS full spectrum was used for vardenafil confir- mm hydrophilic, polypropylene membrane filter obtained from mation. Pall Gelman Laboratory (East Hills, NY). The primary organic component of the mobile phase was HPLC-grade acetonitrile, Calibrator and control preparation which was filtered prior to use through a vacuum filter appa- Calibration curves were prepared by serial dilution utilizing ratus that incorporated the same type of membrane filter de- bovine whole blood as the diluent. Calibrators were prepared scribed. from one original stock standard solution of vardenafil. Con- trois were prepared in a similar manner as calibrators, using Instrumentation and LC-MS method the same bovine whole blood as diluent but employing a second The instrumentation and method development procedures original stock solution. Calibration curves were routinely pre- employed for this study were identical to those used in other pared at a concentration range of 0.39-200 ng/mL. A min- recently published work from our laboratory (14). Briefly, how- imum of seven calibrators was used to construct each calibra- ever, identification and quantitation were accomplished using tion curve. Controls used for the determination of accuracy, a Thermo Finnigan model LCQ APCI-IT-MS(Thermo Finnigan precision, and compound stability were prepared at 2, 20, and Corp., San Jose, CA). For all determinations, the HPLC was op- 200 ng/mL. Controls were prepared in pools large enough to erated in an isocratic mode with a flow rate of 1.00 mL/min. provide samples for the entire study. A sildenafil-d8 working The mobile phase ratio employed was 70:30 (acetonitrile/ standard was prepared at a final concentration of 50 ng/mL by buffer).
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