{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T10:48:24Z","timestamp":1777718904363,"version":"3.51.4"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2021,10,3]],"date-time":"2021-10-03T00:00:00Z","timestamp":1633219200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,3]],"date-time":"2021-10-03T00:00:00Z","timestamp":1633219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005690","name":"Universit\u00e4t des Saarlandes","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005690","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>New synthetic opioids (NSOs) pose a public health concern since their emergence on the illicit drug market and are gaining increasing importance in forensic toxicology. Like many other new psychoactive substances, NSOs are consumed without any preclinical safety data or any knowledge on toxicokinetic (TK) data. Due to ethical reasons, controlled human TK studies cannot be performed for the assessment of these relevant data. As an alternative animal experimental approach, six pigs per drug received a single intravenous dose of 100\u00a0\u00b5g\/kg body weight (BW) of U-47700 or 1000\u00a0\u00b5g\/kg BW of tramadol to evaluate whether this species is suitable to assess the TK of NSOs. The drugs were determined in serum and whole blood using a fully validated method based on solid-phase extraction and LC\u2013MS\/MS. The concentration\u2013time profiles and a population (pop) TK analysis revealed that a three-compartment model best described the TK data of both opioids. Central volumes of distribution were 0.94 L\/kg for U-47700 and 1.25 L\/kg for tramadol and central (metabolic) clearances were estimated at 1.57 L\/h\/kg and 1.85 L\/h\/kg for U-47700 and tramadol, respectively. The final popTK model parameters for pigs were upscaled via allometric scaling techniques. In comparison to published human data, concentration\u2013time profiles for tramadol could successfully be predicted with single species allometric scaling. Furthermore, possible profiles for U-47700 in humans were simulated. The findings of this study indicate that unlike a multiple species scaling approach, pigs in conjunction with TK modeling are a suitable tool for the assessment of TK data of NSOs and the prediction of human TK data.<\/jats:p>","DOI":"10.1007\/s00204-021-03169-y","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T18:38:37Z","timestamp":1633372717000},"page":"3681-3693","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Toxicokinetics of U-47700, tramadol, and their main metabolites in pigs following intravenous administration: is a multiple species allometric scaling approach useful for the extrapolation of toxicokinetic parameters to humans?"],"prefix":"10.1007","volume":"95","author":[{"given":"Frederike","family":"Nordmeier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iryna","family":"Sihinevich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian A.","family":"Doerr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadja","family":"Walle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias W.","family":"Laschke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thorsten","family":"Lehr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Menger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter H.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus R.","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5589-9370","authenticated-orcid":false,"given":"Nadine","family":"Schaefer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,10,3]]},"reference":[{"issue":"10","key":"3169_CR1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.1791","volume":"9","author":"SK Alzghari","year":"2017","unstructured":"Alzghari SK, Fleming SW, Rambaran KA et al (2017) U-47700: An emerging threat. Cureus 9(10):e1791. https:\/\/doi.org\/10.7759\/cureus.1791","journal-title":"Cureus"},{"key":"3169_CR2","first-page":"56","volume":"26","author":"P Anzenbacher","year":"1998","unstructured":"Anzenbacher P, Soucek P, Anzenbacherova E et al (1998) Presence and activity of cytochrome P450 isoforms in minipig liver microsomes comparison with human liver samples. Drug Metab Dispos 26:56\u201359","journal-title":"Drug Metab Dispos"},{"key":"3169_CR3","volume-title":"Nonmem user\u2019s guides","author":"SL Beal","year":"2009","unstructured":"Beal SL, Boeckmann A, Bauer RJ (2009) Nonmem user\u2019s guides. Icon Development Solutions, Ellicott City"},{"issue":"3","key":"3169_CR4","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.tvjl.2015.04.011","volume":"205","author":"E Bortolami","year":"2015","unstructured":"Bortolami E, Della Rocca G, Di Salvo A et al (2015) Pharmacokinetics and antinociceptive effects of tramadol and its metabolite O-desmethyltramadol following intravenous administration in sheep. Vet J 205(3):404\u2013409. https:\/\/doi.org\/10.1016\/j.tvjl.2015.04.011","journal-title":"Vet J"},{"key":"3169_CR5","doi-asserted-by":"publisher","first-page":"3S","DOI":"10.1016\/S0952-8180(97)00119-0","volume":"9","author":"JG Bovill","year":"1997","unstructured":"Bovill JG (1997) Adverse drug interactions in anesthesia. J Clin Anesth 9:3S-13S. https:\/\/doi.org\/10.1016\/S0952-8180(97)00119-0","journal-title":"J Clin Anesth"},{"key":"3169_CR6","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.clinbiochem.2009.10.001","volume":"43","author":"RAR Bowen","year":"2010","unstructured":"Bowen RAR, Hortin GL, Csako G et al (2010) Impact of blood collection devices on clinical chemistry assays. Clin Biochem 43:4\u201325. https:\/\/doi.org\/10.1016\/j.clinbiochem.2009.10.001","journal-title":"Clin Biochem"},{"key":"3169_CR7","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/BF01065191","volume":"8","author":"H Boxenbaum","year":"1980","unstructured":"Boxenbaum H (1980) Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: Extrapolation of data to benzodiazepines and phenytoin. J Pharmacokinet Biopharm 8:165\u2013176. https:\/\/doi.org\/10.1007\/BF01065191","journal-title":"J Pharmacokinet Biopharm"},{"key":"3169_CR8","doi-asserted-by":"publisher","unstructured":"Campanero MA, Calahorra B, Valle M, et al (1999) Enantiomeric separation of tramadol and its active metabolite in human plasma by chiral high-performance liquid chromatography: Application to pharmacokinetic studies. Chirality 11:272\u2013279. https:\/\/doi.org\/10.1002\/(SICI)1520-636X(1999)11:4<272::AID-CHIR3>3.0.CO;2-I","DOI":"10.1002\/(SICI)1520-636X(1999)11:4<272::AID-CHIR3>3.0.CO;2-I"},{"key":"3169_CR9","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/J.FORSCIINT.2016.05.001","volume":"266","author":"V Coopman","year":"2016","unstructured":"Coopman V, Blanckaert P, Van Parys G, Van Calenbergh S, Cordonnier J (2016) A case of acute intoxication due to combined use of fentanyl and 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700). Forensic Sci Int 266:68\u201372. https:\/\/doi.org\/10.1016\/J.FORSCIINT.2016.05.001","journal-title":"Forensic Sci Int"},{"key":"3169_CR10","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1111\/j.1365-2885.2010.01219.x","volume":"34","author":"S Cox","year":"2011","unstructured":"Cox S, Mart\u00edn-Jim\u00e9nez T, Amstel S, Doherty T (2011) Pharmacokinetics of intravenous and intramuscular tramadol in llamas. J Vet Pharmacol Ther 34:259\u2013264. https:\/\/doi.org\/10.1111\/j.1365-2885.2010.01219.x","journal-title":"J Vet Pharmacol Ther"},{"key":"3169_CR11","doi-asserted-by":"publisher","first-page":"157","DOI":"10.4155\/fmc-2020-0187","volume":"13","author":"RP Dash","year":"2020","unstructured":"Dash RP, Veeravalli V, Thomas JA et al (2020) Whole blood or plasma: what is the ideal matrix for pharmacokinetic-driven drug candidate selection? Future Med Chem 13:157\u2013171. https:\/\/doi.org\/10.4155\/fmc-2020-0187","journal-title":"Future Med Chem"},{"key":"3169_CR12","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1002\/cpdd.378","volume":"6","author":"B DeLemos","year":"2017","unstructured":"DeLemos B, Richards HM, Vandenbossche J et al (2017) Safety, tolerability, and pharmacokinetics of therapeutic and supratherapeutic doses of tramadol hydrochloride in healthy adults: A randomized, double-blind, placebo-controlled multiple-ascending-dose study. Clin Pharmacol Drug Dev 6:592\u2013603. https:\/\/doi.org\/10.1002\/cpdd.378","journal-title":"Clin Pharmacol Drug Dev"},{"key":"3169_CR13","unstructured":"EMCDDA: European Monitoring Center of Drugs and Drug Addiction (2019) European drug report \u2013 Trends and developments. http:\/\/www.emcdda.europa.eu\/system\/files\/publications\/11364\/20191724_TDAT19001ENN_PDF.pdf. Accessed March 2021"},{"key":"3169_CR14","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.vaa.2016.09.007","volume":"45","author":"R Evangelista Vaz","year":"2018","unstructured":"Evangelista Vaz R, Draganov DI, Rapp C et al (2018) Preliminary pharmacokinetics of tramadol hydrochloride after administration via different routes in male and female B6 mice. Vet Anaesth Analg 45:111\u2013122. https:\/\/doi.org\/10.1016\/j.vaa.2016.09.007","journal-title":"Vet Anaesth Analg"},{"issue":"3","key":"3169_CR15","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1093\/jat\/bkw131","volume":"41","author":"SW Fleming","year":"2017","unstructured":"Fleming SW, Cooley JC, Johnson L et al (2017) Analysis of U-47700, a novel synthetic opioid, in human urine by LC-MS-MS and LC-QToF. J Anal Toxicol 41(3):173\u2013180. https:\/\/doi.org\/10.1093\/jat\/bkw131","journal-title":"J Anal Toxicol"},{"issue":"2","key":"3169_CR16","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1111\/j.1365-2885.1981.tb00715.x","volume":"4","author":"R Garcia-Villar","year":"1981","unstructured":"Garcia-Villar R, Toutain PL, Alvinerie M, Ruckenbusch Y (1981) The pharmacokinetics of xylazine hydrochloride: an interspecific study. J Vet Pharmacol Ther 4(2):87\u201392. https:\/\/doi.org\/10.1111\/j.1365-2885.1981.tb00715.x","journal-title":"J Vet Pharmacol Ther"},{"issue":"4","key":"3169_CR17","doi-asserted-by":"publisher","first-page":"639","DOI":"10.2478\/v10181-010-0027-y","volume":"13","author":"M Giorgi","year":"2010","unstructured":"Giorgi M, Del Carlo S, \u0141ebkowska-Wieruszewska B, Kowalski CJ, Saccomanni G (2010) Pharmacokinetics of tramadol and metabolites after injective administrations in dogs. Pol J Vet Sci 13(4):639\u2013644. https:\/\/doi.org\/10.2478\/v10181-010-0027-y","journal-title":"Pol J Vet Sci"},{"key":"3169_CR18","doi-asserted-by":"publisher","first-page":"879","DOI":"10.2165\/00003088-200443130-00004","volume":"43","author":"S Grond","year":"2004","unstructured":"Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43:879\u2013923. https:\/\/doi.org\/10.2165\/00003088-200443130-00004","journal-title":"Clin Pharmacokinet"},{"issue":"3","key":"3169_CR19","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1002\/jps.22811","volume":"101","author":"C Hall","year":"2012","unstructured":"Hall C, Lueshen E, Mo\u0161at\u2019 A, Linninger AA, (2012) Interspecies scaling in pharmacokinetics: A novel whole-body physiologically based modeling framework to discover drug biodistribution mechanisms in vivo. J Pharm Sci 101(3):1221\u20131241. https:\/\/doi.org\/10.1002\/jps.22811","journal-title":"J Pharm Sci"},{"issue":"3","key":"3169_CR20","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1111\/jvp.12174","volume":"38","author":"Q Huang","year":"2015","unstructured":"Huang Q, Gehring R, Tell LA, Li M, Riviere JE (2015) Interspecies allometric meta-analysis of the comparative pharmacokinetics of 85 drugs across veterinary and laboratory animal species. J Vet Pharmacol Ther 38(3):214\u2013226. https:\/\/doi.org\/10.1111\/jvp.12174","journal-title":"J Vet Pharmacol Ther"},{"key":"3169_CR21","doi-asserted-by":"publisher","first-page":"972","DOI":"10.3109\/00498254.2011.598582","volume":"41","author":"Y Huh","year":"2011","unstructured":"Huh Y, Smith DE, Rose Feng M (2011) Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs. Xenobiotica 41:972\u2013987. https:\/\/doi.org\/10.3109\/00498254.2011.598582","journal-title":"Xenobiotica"},{"key":"3169_CR22","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1007\/978-3-642-10324-7_6","volume":"199","author":"R Hunter","year":"2010","unstructured":"Hunter R (2010) Interspecies allometric scaling. Handb Exp Pharmacol 199:139\u2013157. https:\/\/doi.org\/10.1007\/978-3-642-10324-7_6","journal-title":"Handb Exp Pharmacol"},{"key":"3169_CR23","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1515\/dmpt-2017-0018","volume":"32","author":"B Jamali","year":"2017","unstructured":"Jamali B, Sheikholeslami B, Hosseinzadeh Ardakani Y et al (2017) Evaluation of the ecstasy influence on tramadol and its main metabolite plasma concentration in rats. Drug Metab Pers Ther 32:137\u2013145. https:\/\/doi.org\/10.1515\/dmpt-2017-0018","journal-title":"Drug Metab Pers Ther"},{"key":"3169_CR24","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1111\/jvp.12194","volume":"38","author":"KR Kelly","year":"2015","unstructured":"Kelly KR, Pypendop BH, Christe KL (2015) Pharmacokinetics of tramadol following intravenous and oral administration in male rhesus macaques (Macaca mulatta). J Vet Pharmacol Ther 38:375\u2013382. https:\/\/doi.org\/10.1111\/jvp.12194","journal-title":"J Vet Pharmacol Ther"},{"key":"3169_CR25","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1097\/00000542-199903000-00019","volume":"90","author":"ED Kharasch","year":"1999","unstructured":"Kharasch ED, Hankins DC, Cox K (1999) Clinical isoflurane metabolism by cytochrome P450 2E1. Anesthesiology 90:766\u2013771. https:\/\/doi.org\/10.1097\/00000542-199903000-00019","journal-title":"Anesthesiology"},{"key":"3169_CR26","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1111\/j.2042-3306.2012.00688.x","volume":"45","author":"HK Knych","year":"2013","unstructured":"Knych HK, Corado CR, Mckemie DS, Steffey EP (2013) Pharmacokinetics and selected pharmacodynamic effects of tramadol following intravenous administration to the horse. Equine Vet J 45:490\u2013496. https:\/\/doi.org\/10.1111\/j.2042-3306.2012.00688.x","journal-title":"Equine Vet J"},{"issue":"8","key":"3169_CR27","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1002\/dta.2391","volume":"10","author":"K Koch","year":"2018","unstructured":"Koch K, Auwaerter V, Hermanns-Clausen M, Wilde M, Neumann MA (2018) Mixed intoxication by the synthetic opioid U-47700 and the benzodiazepine flubromazepam with lethal outcome: Pharmacokinetic data. Drug Test Anal 10(8):1336\u20131341. https:\/\/doi.org\/10.1002\/dta.2391","journal-title":"Drug Test Anal"},{"issue":"1","key":"3169_CR28","first-page":"36","volume":"85","author":"S Lehmann","year":"2018","unstructured":"Lehmann S, Teifel D, Rothschild MA, Andresen-Streichert H (2018) T\u00f6dliche Intoxikation mit dem Designer-Opioid U-47700. Tochichem Krimtech 85(1):36","journal-title":"Tochichem Krimtech"},{"key":"3169_CR29","first-page":"1278","volume":"36","author":"W Lintz","year":"1986","unstructured":"Lintz W, Barth H, Osterloh G, Schmidt-Boethelt E (1986) Bioavailability of enteral tramadol formulations. 1st communication: capsules. Arzneimittelforschung 36:1278\u20131283","journal-title":"Arzneimittelforschung"},{"key":"3169_CR30","first-page":"436","volume":"48","author":"W Lintz","year":"1998","unstructured":"Lintz W, Barth H, Becker R et al (1998a) Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol. Arzneimittelforschung 48:436\u2013445","journal-title":"Arzneimittelforschung"},{"key":"3169_CR31","first-page":"889","volume":"48","author":"W Lintz","year":"1998","unstructured":"Lintz W, Barth H, Osterloh G (1998b) Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 43rd communication: suppositories. Arzneimittelforschung 48:889\u2013899","journal-title":"Arzneimittelforschung"},{"key":"3169_CR32","unstructured":"Gelbe Liste (2020). Pharmindex. https:\/\/www.gelbe-liste.de\/wirkstoffe\/Tramadol_1406. Accessed March 2021"},{"key":"3169_CR33","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1517\/17425255.2.6.875","volume":"2","author":"M Martignoni","year":"2006","unstructured":"Martignoni M, Groothuis GMM, de Kanter R (2006) Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2:875\u2013894. https:\/\/doi.org\/10.1517\/17425255.2.6.875","journal-title":"Expert Opin Drug Metab Toxicol"},{"issue":"13","key":"3169_CR34","doi-asserted-by":"publisher","first-page":"3019","DOI":"10.1021\/ac020361s","volume":"75","author":"BK Matuszewski","year":"2003","unstructured":"Matuszewski BK, Constanzer ML, Chavez-Eng CM (2003) Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS\/MS. Anal Chem 75(13):3019\u20133030. https:\/\/doi.org\/10.1021\/ac020361s","journal-title":"Anal Chem"},{"key":"3169_CR35","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1016\/j.bcp.2015.09.008","volume":"98","author":"MR Meyer","year":"2015","unstructured":"Meyer MR, Rosenborg S, Stenberg M, Beck O (2015) First report on the pharmacokinetics of tramadol and O-desmethyltramadol in exhaled breath compared to plasma and oral fluid after a single oral dose. Biochem Pharmacol 98:502\u2013510. https:\/\/doi.org\/10.1016\/j.bcp.2015.09.008","journal-title":"Biochem Pharmacol"},{"issue":"9","key":"3169_CR36","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1093\/jat\/bkw086","volume":"40","author":"ALA Mohr","year":"2016","unstructured":"Mohr ALA, Friscia M, Papsun D, Kacinko SL, Buzby D, Logan BK (2016) Analysis of novel synthetic opioids U-47700, U-50488 and furanyl fentanyl by LC-MS\/MS in postmortem casework. J Anal Toxicol 40(9):709\u2013717. https:\/\/doi.org\/10.1093\/jat\/bkw086","journal-title":"J Anal Toxicol"},{"key":"3169_CR37","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1093\/oxfordjournals.bja.a013437","volume":"84","author":"B Murthy","year":"2000","unstructured":"Murthy B, Pandya K, Booker P, Murray A, Lintz W, Terlinden R (2000) Pharmacokinetics of tramadol in children after IV or caudal epidural administration. Br J Anaesth 84:346\u2013349. https:\/\/doi.org\/10.1093\/oxfordjournals.bja.a013437","journal-title":"Br J Anaesth"},{"key":"3169_CR38","unstructured":"NeuePsychoaktiveSubstanzen (2017) http:\/\/neuepsychoaktivesubstanzen.de\/u-47700\/#U-47700_Dosis_Dosierung. Accessed March 2021"},{"key":"3169_CR39","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/s00194-020-00424-x","volume":"30","author":"F Nordmeier","year":"2020","unstructured":"Nordmeier F, Doerr A, Laschke MW et al (2020b) Erhebung toxikokinetischer Daten der synthetischen Opioide U-47700 und Tramadol sowie der Hauptmetabolite im Schwein nach intraven\u00f6ser Verabreichung. 99. Jahrestagung der Deutschen Gesellschaft f\u00fcr Rechtsmedizin. Abstracts Rechtsmedizin 30:361\u2013412","journal-title":"Abstracts Rechtsmedizin"},{"key":"3169_CR40","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.toxlet.2020.04.001","volume":"329","author":"F Nordmeier","year":"2020","unstructured":"Nordmeier F, Doerr A, Laschke MW et al (2020) Are pigs a suitable animal model for in vivo metabolism studies of new psychoactive substances? A comparison study using different in vitro\/in vivo tools and U-47700 as model drug. Toxicol Lett 329:12\u201319. https:\/\/doi.org\/10.1016\/j.toxlet.2020.04.001","journal-title":"Toxicol Lett"},{"key":"3169_CR41","doi-asserted-by":"publisher","DOI":"10.1093\/jat\/bkab044","author":"F Nordmeier","year":"2021","unstructured":"Nordmeier F, Doerr AA, Potente S et al (2021) Perimortem distribution of U-47700, tramadol and their main metabolites in pigs following intravenous administration. J Anal Toxicol. https:\/\/doi.org\/10.1093\/jat\/bkab044","journal-title":"J Anal Toxicol"},{"key":"3169_CR42","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/J.FORSCIINT.2006.05.021","volume":"165","author":"FT Peters","year":"2007","unstructured":"Peters FT, Drummer OH, Musshoff F (2007) Validation of new methods. Forensic Sci Int 165:216\u2013224. https:\/\/doi.org\/10.1016\/J.FORSCIINT.2006.05.021","journal-title":"Forensic Sci Int"},{"key":"3169_CR43","unstructured":"Peters F, Paul L, Musshoff F, et al (2009) Anhang B zur Richtlinie der GTFCh zur Qualit\u00e4tssicherung bei forensisch-toxikologischen Untersuchungen Anforderungen an die Validierung von Analysemethoden. Toxichem Krimtech. https:\/\/www.gtfch.org\/cms\/images\/stories\/files\/GTFCh_Richtlinie_Anhang B_Validierung_Version 1.pdf. Accessed March 2021"},{"key":"3169_CR44","doi-asserted-by":"publisher","first-page":"507","DOI":"10.2174\/138920011795713698","volume":"12","author":"E Puccinelli","year":"2011","unstructured":"Puccinelli E, Gervasi P, Longo V (2011) Xenobiotic metabolizing cytochrome P450 in pig, a promising animal model. Curr Drug Metab 12:507\u2013525. https:\/\/doi.org\/10.2174\/138920011795713698","journal-title":"Curr Drug Metab"},{"key":"3169_CR45","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1002\/bdd.526","volume":"28","author":"EG Quetglas","year":"2007","unstructured":"Quetglas EG, Azanza JR, Cardenas E et al (2007) Stereoselective pharmacokinetic analysis of tramadol and its main phase I metabolites in healthy subjects after intravenous and oral administration of racemic tramadol. Biopharm Drug Dispos 28:19\u201333. https:\/\/doi.org\/10.1002\/bdd.526","journal-title":"Biopharm Drug Dispos"},{"key":"3169_CR46","volume-title":"R: A language and environment for statistical computing","author":"R.C. Team","year":"2018","unstructured":"R.C. Team (2018) R: A language and environment for statistical computing. R foundation for Statistical computing, Vienna"},{"key":"3169_CR47","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/J.JEMERMED.2017.05.034","volume":"53","author":"KA Rambaran","year":"2017","unstructured":"Rambaran KA, Fleming SW, An J et al (2017) U-47700: A Clinical Review of the Literature. J Emerg Med 53:509\u2013519. https:\/\/doi.org\/10.1016\/J.JEMERMED.2017.05.034","journal-title":"J Emerg Med"},{"issue":"1","key":"3169_CR48","doi-asserted-by":"publisher","first-page":"e12","DOI":"10.1093\/jat\/bkx081","volume":"42","author":"TP Rohrig","year":"2017","unstructured":"Rohrig TP, Miller SA, Baird TR (2017) U-47700: A not so new opioid. J Anal Toxicol 42(1):e12\u2013e14. https:\/\/doi.org\/10.1093\/jat\/bkx081","journal-title":"J Anal Toxicol"},{"key":"3169_CR49","doi-asserted-by":"publisher","first-page":"3775","DOI":"10.1007\/s00216-015-8605-6","volume":"407","author":"N Schaefer","year":"2015","unstructured":"Schaefer N, Kettner M, Laschke MW et al (2015) Simultaneous LC-MS\/MS determination of JWH-210, RCS-4, \u22069-tetrahydrocannabinol, and their main metabolites in pig and human serum, whole blood, and urine for comparing pharmacokinetic data. Anal Bioanal Chem 407:3775\u20133786. https:\/\/doi.org\/10.1007\/s00216-015-8605-6","journal-title":"Anal Bioanal Chem"},{"key":"3169_CR50","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/J.TOXLET.2016.04.021","volume":"253","author":"N Schaefer","year":"2016","unstructured":"Schaefer N, Wojtyniak J-G, Kettner M et al (2016) Pharmacokinetics of (synthetic) cannabinoids in pigs and their relevance for clinical and forensic toxicology. Toxicol Lett 253:7\u201316. https:\/\/doi.org\/10.1016\/J.TOXLET.2016.04.021","journal-title":"Toxicol Lett"},{"key":"3169_CR51","doi-asserted-by":"publisher","first-page":"713","DOI":"10.2174\/1570159X15666161111114214","volume":"15","author":"N Schaefer","year":"2017","unstructured":"Schaefer N, Kettner M, Laschke MW et al (2017) Distribution of synthetic cannabinoids JWH-210, RCS-4 and \u0394 9-tetrahydrocannabinol after intravenous administration to pigs. Curr Neuropharmacol 15:713\u2013723. https:\/\/doi.org\/10.2174\/1570159X15666161111114214","journal-title":"Curr Neuropharmacol"},{"key":"3169_CR52","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/J.BCP.2018.07.029","volume":"155","author":"N Schaefer","year":"2018","unstructured":"Schaefer N, Wojtyniak J-G, Kroell A-K et al (2018) Can toxicokinetics of (synthetic) cannabinoids in pigs after pulmonary administration be upscaled to humans by allometric techniques? Biochem Pharmacol 155:403\u2013418. https:\/\/doi.org\/10.1016\/J.BCP.2018.07.029","journal-title":"Biochem Pharmacol"},{"key":"3169_CR53","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1007\/s00204-020-02707-4","volume":"94","author":"N Schaefer","year":"2020","unstructured":"Schaefer N, Kroell A-K, Koerbel C et al (2020) Time- and temperature-dependent postmortem concentration changes of the (synthetic) cannabinoids JWH-210, RCS-4, as well as \u22069-tetrahydrocannabinol following pulmonary administration to pigs. Arch Toxicol 94:1585\u20131599. https:\/\/doi.org\/10.1007\/s00204-020-02707-4","journal-title":"Arch Toxicol"},{"key":"3169_CR54","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1111\/j.1365-2885.2007.00929.x","volume":"31","author":"Y Shilo","year":"2008","unstructured":"Shilo Y, Britzi M, Eytan B, Lifschitz T, Soback S, Steinmann A (2008) Pharmacokinetics of tramadol in horses after intravenous, intramuscular and oral administration. J Vet Pharmacol Ther 31:60\u201365. https:\/\/doi.org\/10.1111\/j.1365-2885.2007.00929.x","journal-title":"J Vet Pharmacol Ther"},{"key":"3169_CR55","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1007\/s40266-015-0315-4","volume":"32","author":"S Skinner-Robertson","year":"2015","unstructured":"Skinner-Robertson S, Fradette C, Bouchard S, Mouksassi MS, Varin F (2015) Pharmacokinetics of tramadol and O-desmethyltramadol enantiomers following administration of extended-release tablets to elderly and young subjects. Drugs Aging 32:1029\u20131043. https:\/\/doi.org\/10.1007\/s40266-015-0315-4","journal-title":"Drugs Aging"},{"key":"3169_CR56","doi-asserted-by":"publisher","first-page":"654","DOI":"10.3389\/fphar.2018.00654","volume":"9","author":"R Solimini","year":"2018","unstructured":"Solimini R, Pichini S, Pacifici R, Busard\u00f2 FP, Giorgetti R (2018) Pharmacotoxicology of non-fentanyl derived new synthetic opioids. Front Pharmacol 9:654. https:\/\/doi.org\/10.3389\/fphar.2018.00654","journal-title":"Front Pharmacol"},{"key":"3169_CR57","doi-asserted-by":"publisher","first-page":"108195","DOI":"10.1016\/j.neuropharm.2020.108195","volume":"177","author":"MT Truver","year":"2020","unstructured":"Truver MT, Smith CR, Garibay N, Kopajtic TA, Swortwood MJ, Baumann MH (2020) Pharmacodynamics and pharmacokinetics of the novel synthetic opioid, U-47700, in male rats. Neuropharmacology 177:108195. https:\/\/doi.org\/10.1016\/j.neuropharm.2020.108195","journal-title":"Neuropharmacology"},{"key":"3169_CR58","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.jphotobiol.2013.01.011","volume":"120","author":"S Tun\u00e7","year":"2013","unstructured":"Tun\u00e7 S, \u00c7etinkaya A, Duman O (2013) Spectroscopic investigations of the interactions of tramadol hydrochloride and 5-azacytidine drugs with human serum albumin and human hemoglobin proteins. J Photochem Photobiol B Biol 120:59\u201365. https:\/\/doi.org\/10.1016\/j.jphotobiol.2013.01.011","journal-title":"J Photochem Photobiol B Biol"},{"key":"3169_CR59","unstructured":"United States Patent (2018). Intravenous administration of tramadol. US 10,022, 321 B2. Accessed March 2021."},{"key":"3169_CR60","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1111\/jvp.12133","volume":"37","author":"C Vullo","year":"2014","unstructured":"Vullo C, Kim TW, Meligrana M, Marini C, Giorgi M (2014) Pharmacokinetics of tramadol and its major metabolite after intramuscular administration in piglets. J Vet Pharmacol Ther 37:603\u2013606. https:\/\/doi.org\/10.1111\/jvp.12133","journal-title":"J Vet Pharmacol Ther"},{"key":"3169_CR61","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1124\/dmd.32.6.603","volume":"32","author":"KW Ward","year":"2004","unstructured":"Ward KW, Smith BR (2004) A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. I Clearance Drug Metab Dispos 32:603\u2013611. https:\/\/doi.org\/10.1124\/dmd.32.6.603","journal-title":"I Clearance Drug Metab Dispos"},{"key":"3169_CR62","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-98141-3","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"H Wickham","year":"2009","unstructured":"Wickham H (2009) ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag, New York"},{"issue":"6","key":"3169_CR63","first-page":"260","volume":"24","author":"J Wieber","year":"1975","unstructured":"Wieber J, Gugler R, Hengstmann JH, Dengler HJ (1975) Pharmacokinetics of ketamine in man. Anaesthesist 24(6):260\u2013263","journal-title":"Anaesthesist"},{"key":"3169_CR64","doi-asserted-by":"publisher","first-page":"287","DOI":"10.2165\/00003088-198815050-00002","volume":"15","author":"KW Woodhouse","year":"1988","unstructured":"Woodhouse KW, Wynne HA (1988) Age-related changes in liver size and hepatic blood flow. Clin Pharmacokinet 15:287\u2013294. https:\/\/doi.org\/10.2165\/00003088-198815050-00002","journal-title":"Clin Pharmacokinet"},{"key":"3169_CR65","unstructured":"World Health Organization (2014), Expert committee on drug dependence thirty\u2010sixth meeting. Tramado l update review report agenda item 6.1. https:\/\/www.who.int\/medicines\/areas\/quality_safety\/6_1_Update.pdf. Accessed March 2021"},{"key":"3169_CR66","unstructured":"World Health Organization (2016) Expert committee on drug dependence thirty-eighth meeting. U-47700 critical review report agenda item 4.1. https:\/\/www.who.int\/medicines\/access\/controlled-substances\/4.1_U-47700_CritReview.pdf?ua=1. Accessed March 2021"},{"key":"3169_CR67","doi-asserted-by":"publisher","first-page":"56","DOI":"10.5740\/jaoacint.14-085","volume":"98","author":"B Y\u0131lmaz","year":"2015","unstructured":"Y\u0131lmaz B, Erdem AF (2015) Simultaneous determination of tramadol and its metabolite in human Plasma by GC\/MS. J AOAC Int 98:56\u201361. https:\/\/doi.org\/10.5740\/jaoacint.14-085","journal-title":"J AOAC Int"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-021-03169-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-021-03169-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-021-03169-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T17:02:49Z","timestamp":1634922169000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-021-03169-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,3]]},"references-count":67,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["3169"],"URL":"https:\/\/doi.org\/10.1007\/s00204-021-03169-y","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,3]]},"assertion":[{"value":"5 July 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that there are no financial or other relations that could lead to a conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"All experiments were performed in accordance with the German legislation on protection of animals and the National Institutes of Health Guide for the Care and Use of Laboratory Animals (permission number: 32\/2018).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}