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Cyclopropylfentanyl is a fentanyl analog associated with many overdose deaths, but limited knowledge is available about its pharmacology. In the present study, we developed a bioanalytical method for the determination of cyclopropylfentanyl and its main metabolite cyclopropylnorfentanyl and evaluated pharmacokinetic-pharmacodynamic relationships in rats.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Method<\/jats:title>\n                <jats:p>An ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS\/MS) method was developed and validated for determination of cyclopropylfentanyl and cyclopropylnorfentanyl in rat plasma. Male Sprague\u2013Dawley rats fitted with jugular catheters and temperature transponders received cyclopropylfentanyl (30, 100, and 300\u00a0\u03bcg\/kg) or saline subcutaneously. Blood specimens were withdrawn over an 8-h time period, along with measurements of pharmacodynamic endpoints.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The analytical method was validated, and both analytes exhibited a low limit of quantification (15\u00a0pg\/mL). Cyclopropylfentanyl caused dose-related increases in hot plate latency (ED<jats:sub>50<\/jats:sub>\u2009=\u200948\u00a0\u00b5g\/kg) and catalepsy (ED<jats:sub>50<\/jats:sub>\u2009=\u200987\u00a0\u00b5g\/kg) and produced long-lasting hypothermia at the highest dose. Plasma cyclopropylfentanyl rose rapidly in a dose-related fashion, reaching maximal concentration (C<jats:sub>max<\/jats:sub>) after 15\u201328\u00a0min, whereas metabolite Cmax occurred later at 45\u201390\u00a0min. Cyclopropylfentanyl C<jats:sub>max<\/jats:sub> values were similar to concentrations measured in non-fatal intoxications in humans; however, differences in parent drug: metabolite ratio indicated possible interspecies variance in metabolism.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our study shows that cyclopropylfentanyl produces typical opioid-like effects in male rats. Cyclopropylfentanyl displays much greater analgesic potency when compared to morphine, suggesting that cyclopropylfentanyl poses increased overdose risk for unsuspecting users.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00213-021-05981-x","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T08:17:48Z","timestamp":1633594668000},"page":"3629-3641","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats"],"prefix":"10.1007","volume":"238","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3171-3906","authenticated-orcid":false,"given":"Marianne Skov-Skov","family":"Bergh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inger Lise","family":"Bogen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Garibay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael H.","family":"Baumann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,10,6]]},"reference":[{"key":"5981_CR1","unstructured":"AAFS (American Academy of Forensic Sciences) (2019) Academy Standards Board (ASB), ANSI\/ASB Standard 036, Standard practices for method validation in forensic toxicology, First Edition. http:\/\/www.asbstandardsboard.org\/wp-content\/uploads\/2019\/11\/036_Std_e1.pdf. 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