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An Interlaboratory Study of the Pharmacokinetics of Testosterone Following Intramuscular Administration to Thoroughbred Horses

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An Interlaboratory Study of the Pharmacokinetics of Testosterone Following Intramuscular Administration to Thoroughbred Horses J. vet. Pharmacol. Therap. doi: 10.1111/j.1365-2885.2011.01277.x An interlaboratory study of the pharmacokinetics of testosterone following intramuscular administration to Thoroughbred horses B. C. MOELLER* Moeller, B. C., Sams, R. A., Guinjab, J., Szabo, N., Colahan, P., Stanley, S. D. An R. A. SAMS interlaboratory study of the pharmacokinetics of testosterone following intramuscular administration to Thoroughbred horses. J. vet. Pharmacol. J. GUINJAB Therap. doi: 10.1111/j.1365-2885.2011.01277.x. N. SZABO P. COLAHANà & Testosterone is an anabolic androgenic steroid (AAS) that is endogenously S. D. STANLEY* produced by both male and female horses that also has the potential for abuse when administered exogenously to race horses. To recommend appropriate *K.L. Maddy Equine Analytical Chemistry withdrawal guidelines so that veterinarians can discontinue therapeutic use Laboratory, California Animal Health and prior to competition, the pharmacokinetics and elimination of testosterone were Food Safety Laboratory, School of investigated. An aqueous testosterone suspension was administered intramus- Veterinary Medicine, University of cularly in the neck of Thoroughbred horses (n = 20). The disposition of California at Davis, Davis, CA, USA; testosterone from this formulation was characterized by an initial, rapid Florida Racing Laboratory, College of absorption phase followed by a much more variable secondary absorption Veterinary Medicine, University of Florida, phase. The median terminal half-life was 39 h. A second focus of this study was Gainesville, FL, USA; àDepartment of Large Animal Clinical Sciences, College of to compare the testosterone concentrations determined by two different Veterinary Medicine, Gainesville, FL, USA laboratories using a percentage similarity model with a coefficient of variation of 16.5% showing good agreement between the two laboratories results. Based on the results of this study, a withdrawal period of 30 days for aqueous testosterone administered IM is recommended. (Paper received 7 May 2010; accepted for publication 7 January 2011) Scott D. Stanley, K.L. Maddy Equine Analytical Chemistry Laboratory, University of California at Davis, West Health Science Drive, Davis, CA 95616, USA. E-mail: [email protected] INTRODUCTION Dumasia, 1979; Thompson et al., 1980; Dumasia & Houghton, 1981; Bonnaire et al., 1995). However, many of these studies Testosterone is an anabolic androgenic steroid (AAS) used in the focused on either the determination of testosterone administra- horse and is classified as a Class 3 drug by the Association tion or the pharmacodynamic effects of the drug. To the best Racing Commissioners International (ARCI). It is a potent sex of the authors’ knowledge, there is only one previous steroid hormone that is produced endogenously in varying report describing the pharmacokinetics of testosterone describing degrees by both intact male and female horses (Silberzahn et al., the administration of testosterone enanthate to eight horses 1983; Inoue et al., 1993; Bonnaire et al., 1995; Roser, 2008). (Martinez et al., 1991). Testosterone is available in several different pharmaceutical With the advent of more sensitive analytical instrumentation formulations and is recommended for use in veterinary medicine used in testosterone analysis, specificity has increased and limits to treat chronic wasting conditions and improve appetite and of detection (LOD) and limits of quantitation (LOQ) have physical appearance. In addition, veterinary compounding improved when compared to previously used radioimmunoassay pharmacies offer for sale numerous testosterone ester prepara- (RIA) (Thompson et al., 1980; Martinez et al., 1991) and gas tions in oil and testosterone suspension in aqueous vehicle. chromatography–mass spectrometry (Houghton & Dumasia, Recent published reviews describing the effects of testosterone 1979; Bonnaire et al., 1995) methods. The improvements from and other AAS have found little evidence for their continued use. these methodologies may ultimately allow for longer detection This is simply because of a the lack of studies showing efficacy or periods following testosterone administration. enhancement of performance along with the strong negative Because of the lack of information detailing the pharmacoki- correlation on breeding careers of horses (Berndtson et al., 1979; netics of testosterone, a study was undertaken to determine the Squires et al., 1982; Maher et al., 1983; Pitts & Davis, 2007; Fajt pharmacokinetics of aqueous testosterone following IM admin- & McCook, 2008). istration. In the United States, there are several regulatory Several studies characterizing the pharmacokinetics of testos- laboratories responsible for testing samples collected from terone in the horse have been undertaken (Houghton & performance horses. Each laboratory may utilize different Ó 2011 Blackwell Publishing Ltd 1 2 B. C. Moeller et al. technologies and techniques and have differing capabilities. concentration from different preparations. HPLC grade solvents Therefore, a secondary goal of this study was to compare results including methanol and methyl-tert-butyl ether (MTBE) were obtained from concurrent analysis of plasma testosterone purchased from Fisher Scientific (Fairlawn, NJ, USA). Deionized concentrations by two analytical laboratories. Information water used for dilutions was generated in house using a Millipore obtained from these studies will be used to develop withdrawal water purification system (Millipore, Billerica, MA, USA). guidelines. For samples analyzed at UCD, separate working solutions used for the generation of calibrators and QCs were used. Testosterone and d3-testosterone (IS) were purchased as powders from Steraloids (Newport, RI, USA), and a 1.0 mg ⁄ mL solution of MATERIALS AND METHODS testosterone was purchased from Cerilliant. Testosterone from Steraloids was used in the generation of calibrators, and Animals testosterone from Cerilliant was used in the generation of QCs. Twenty healthy adult Thoroughbred horses (13 geldings and Acetonitrile, MTBE, methanol, and water were HPLC grade and seven mares with a mean ± SD weight of 534.1 ± 43.1 kg and purchased from Burdick and Jackson (Muskegon, MI, USA). an age of 7.0 ± 1.8 years) were selected for the study. All horses Acetone, isopropanol, and ammonium hydroxide were Optima were considered fit, as assessed by the ability to run one mile in grade and purchased from ThermoFisher (St Louis, MO, USA). 2 min without undue stress. Food and water were available ACS grade formic acid was purchased from EMD (Gibbstown, NJ, ad libitum throughout the study. Horses did not receive any USA). medications for at least 2 weeks prior to commencement of this study. Administrations for this study were conducted at the Sample analysis University of Florida (UF), and the study was approved by the Institutional Animal Care and Use Committee. Plasma samples were analyzed in racing chemistry laboratories located at the UF and the UCD. Samples were analyzed in both laboratories’ using liquid–liquid extraction (LLE) and quantified Drug administration by high-performance liquid chromatography–tandem mass spec- Horses received a single IM injection in the neck of 0.15 mg ⁄ kg trometry (LC-MS ⁄ MS) using a triple quadrupole mass spectrom- of an aqueous compounded testosterone suspension (75 mg ⁄ mL; eter with electrospray ionization operating in the positive mode. Franck’s Pharmacy, Ocala, FL, USA). Each horse was weighed Both laboratories independently developed and validated analyt- prior to drug administration. ical methods to quantify testosterone. Both laboratories methods assessed inter- ⁄ intra-assay precision and accuracy, analyte recovery, ion suppression, assay linearity, and analyte stability Sample collection (freeze ⁄ thaw and long term) during the validation of the methods Blood samples were collected immediately before (predose and the results met guidelines outlined by the Food and Drug control) and at 1, 2, 4, 6, 8, and 24 h, and at 2, 3, 4, 5, 7, 9, Administration (FDA) guidelines for bioanalysis (FDA, 2001). 11, 14, 17, 21, 25, 28, and 34 days postdrug administration. Both laboratories used Thermo triple stage quadrupole mass Blood samples were collected from each horse until there were at spectrometers that were controlled using Xcalibur 2.0 or 2.07 least two consecutive samples with no detectable testosterone. software (Thermo Scientific, San Jose, CA, USA). The UF used a Blood samples were collected into lithium heparin blood tubes method targeting only testosterone while the UCD laboratory (15 USP units; Becton Dickinson, Franklin Lakes, NJ, USA) and used a multiple analyte method to quantify testosterone along stored on ice until centrifugation at 1300 g at 4 °C for 15 min. with three additional AAS. Plasma was immediately transferred into cryovials (Phenix UCD employed a LC-MS ⁄ MS system consisting of a TSQ Research Products, Chandler, NC, USA) and stored at )70 °C Vantage triple quad mass spectrometer (Thermo, San Jose, CA, until analysis. Plasma samples were split with one set shipped USA) equipped with a TLX2 turbulent flow chromatography frozen by overnight courier to the University of California – Davis HPLC system (ThermoFisher Scientific Inc., Franklin, MA, USA). (UCD) for analysis and the remaining set being analyzed at UF. This method was developed and validated with the details of this method reported elsewhere (Moeller et al., 2010). Briefly, 1 mL of plasma fortified with an IS of d3-testosterone was extracted by
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