{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T15:45:54Z","timestamp":1758815154115,"version":"3.40.5"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019415","name":"H. Wilhelm Schaumann Stiftung","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100019415","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Richter Pharma AG"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>This preliminary clinical investigation of the pharmacokinetic behavior of the main metamizole (dipyrone) metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) in calves undergoing umbilical surgery is part of an already published main study. A single intravenous dose of metamizole was added to ketamine\/xylazine\/isoflurane anesthesia. Eight Simmental calves weighing 90 \u00b1 10.8 kg and aged 47.6 \u00b1 10.4 days received 40 mg\/kg metamizole intravenously 10 minutes prior to general anesthesia. Blood samples were collected over 24 hours and analyzed for 4-MAA and 4-AA. Meloxicam was additionally given twice: 2.5 hours pre- and 20.5 hours postsurgically. The pharmacokinetic profile of 4-MAA was best fitted to a two-compartment model and was characterized by a fast distribution half-life and slow elimination half-life (t<jats:sub>\u00bdalpha<\/jats:sub> = 5.29 minutes, t<jats:sub>\u00bdbeta<\/jats:sub> = 9.49 hours). The maximum concentration (C<jats:sub>max<\/jats:sub> 101.63 \u03bcg\/mL) was detected at the first measurement time point 15 minutes after administration. In contrast, 4-AA showed fast, high and biphasic plasma peak concentration behavior in five calves (2.54\u20132.66 \u03bcg\/mL after 15\u201330 minutes, and 2.10\u20132.14 \u03bcg\/mL after 2\u20133.5 hours) with a t<jats:sub>\u00bdbeta<\/jats:sub> of 8.87 hours, indicating a rapid distribution and subsequent redistribution from well-perfused organs. Alternatively, three calves exhibited a slower and lower monophasic plasma peak concentration (1.66 \u03bcg\/mL after 6.5 hours) with a t<jats:sub>\u00bdbeta<\/jats:sub> of 6.23 hours, indicating slow accumulation in the intravascular compartment. The maximum concentration and area under the plasma concentration curve (AUC) of 4-AA were lower than those of 4-MAA. This metabolic behavior supports our already published data on clinical monitoring and plasma cortisol concentrations (PCCs). Compared to those of saline controls, lower PCCs correspond to the t<jats:sub>\u00bdalpha<\/jats:sub> of 4-MAA. Data on T<jats:sub>max<\/jats:sub> and t<jats:sub>\u00bdbeta<\/jats:sub> also match these clinical observations. However, further studies are required to assess the exact analgesic mechanism and potency of the metamizole metabolites in calves.<\/jats:p>","DOI":"10.1371\/journal.pone.0265305","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T17:26:32Z","timestamp":1647365192000},"page":"e0265305","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Pharmacokinetics of metamizole (dipyrone) as an add-on in calves undergoing umbilical surgery"],"prefix":"10.1371","volume":"17","author":[{"given":"Daniela","family":"Fux","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0752-6059","authenticated-orcid":true,"given":"Moritz","family":"Metzner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna","family":"Brandl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Feist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Behrendt-Wippermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"von Thaden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6133-5099","authenticated-orcid":true,"given":"Christine","family":"Baumgartner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"key":"pone.0265305.ref001","first-page":"315","article-title":"Comparison of three different anesthesia procedures in calves with respect to possible pain-associated reactions","volume":"125","author":"A Hefti","year":"2012","journal-title":"Berl Munch Tierarztl Wochenschr"},{"key":"pone.0265305.ref002","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1467-2995.2011.00698.x","article-title":"Comparison of isoflurane inhalation anaesthesia, injection anaesthesia and high volume caudal epidural anaesthesia for umbilical surgery in calves; metabolic, endocrine and cardiopulmonary effects","volume":"39","author":"J Offinger","year":"2012","journal-title":"Vet Anaesth Analg"},{"key":"pone.0265305.ref003","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.cvfa.2016.05.002","article-title":"Field sedation and anesthesia of ruminats","volume":"32","author":"R Seddighi","year":"2016","journal-title":"Vet Clin Food Anim"},{"key":"pone.0265305.ref004","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S0749-0720(15)30391-1","article-title":"General Anesthetic Techniques in Ruminants","volume":"12","author":"GL Carroll","year":"1996","journal-title":"Vet Clin North Am Food Anim Pract"},{"key":"pone.0265305.ref005","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1365-2885.1984.tb00888.x","article-title":"The pharmacokinetics of ketamine administered intravenously in calves and the modifying effect of premedication with xylazine hydrochloride","volume":"7","author":"AE Waterman","year":"1984","journal-title":"J Vet Pharmacol Ther"},{"key":"pone.0265305.ref006","doi-asserted-by":"crossref","first-page":"472","DOI":"10.4103\/0970-9185.119137","article-title":"Post-operative analgesia for major abdominal surgery and its effectiveness in a tertiary care hospital","volume":"29","author":"A Ahmed","year":"2013","journal-title":"J Anaesthesiol Clin Pharmacol"},{"key":"pone.0265305.ref007","unstructured":"Bundes\u00e4rztekammer, Arzneimittelkommission der Deutschen \u00c4rzteschaft: \u201cAus der UAW-Datenbank\u201d Agranulozytose nach Metamizol\u2014sehr selten, aber h\u00e4ufiger als gedacht, Dtsch Arztebl 2011; 108(33): A-1758 \/ B-1498 \/ C-1494"},{"key":"pone.0265305.ref008","unstructured":"FDA. 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