{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:22:42Z","timestamp":1760145762638,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T00:00:00Z","timestamp":1724198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003359","name":"Conselleria d\u2019Innovaci\u00f3, Universitats, Ci\u00e8ncia i Societat Digital of the Generalitat Valenciana","doi-asserted-by":"publisher","award":["GV\/2018\/049","CIGE\/2022\/148"],"award-info":[{"award-number":["GV\/2018\/049","CIGE\/2022\/148"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic\u2013pharmacodynamic (PK\u2013PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg\/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK\u2013PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL\/kg and CL = 4.5 \u00d7 10\u22121 mL\/h\/kg). A precursor-pool PK\u2013PD model (kin = 6.1 \u00d7 10\u22123 mg\/h, kp = 8.6 \u00d7 10\u22124 h\u22121 and kout = 2.7 \u00d7 10\u22122 h\u22121) with a parallel transit chain (k0 = 1.9 \u00d7 10\u22121 h\u22121) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope1 = 1.1 \u00d7 10\u22121 h) and the elimination of MA (Slope2 = 1.25 h) through the transit chain. Regarding the reference dose (1 mg\/kg) of the RIM model, the administration of 4 mg\/kg would lead to a mean reduction of 65% (Cmax), 80% (Cmin), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.<\/jats:p>","DOI":"10.3390\/pharmaceutics16081101","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T03:07:38Z","timestamp":1724296058000},"page":"1101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Population Pharmacokinetic\u2013Pharmacodynamic Analysis of a Reserpine-Induced Myalgia Model in Rats"],"prefix":"10.3390","volume":"16","author":[{"given":"Gloria M.","family":"Alfosea-Cuadrado","sequence":"first","affiliation":[{"name":"Department of Human Anatomy and Embryology, University of Valencia, 46010 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4799-9076","authenticated-orcid":false,"given":"Javier","family":"Zarzoso-Foj","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100 Valencia, Spain"},{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0570-4931","authenticated-orcid":false,"given":"Albert","family":"Adell","sequence":"additional","affiliation":[{"name":"Systems Neurobiology, Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), Spanish National Research Council (CSIC), 39011 Santander, Spain"},{"name":"Biomedical Research Networking Centre for Mental Health (CIBERSAM), 39011 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfonso A.","family":"Valverde-Navarro","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Embryology, University of Valencia, 46010 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4092-6962","authenticated-orcid":false,"given":"Eva M.","family":"Gonz\u00e1lez-Soler","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Embryology, University of Valencia, 46010 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3388-5023","authenticated-orcid":false,"given":"V\u00edctor","family":"Mangas-Sanju\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100 Valencia, Spain"},{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4040-3117","authenticated-orcid":false,"given":"Arantxa","family":"Blasco-Serra","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Embryology, University of Valencia, 46010 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/s41584-020-00506-w","article-title":"Fibromyalgia: An Update on Clinical Characteristics, Aetiopathogenesis and Treatment","volume":"16","author":"Giorgi","year":"2020","journal-title":"Nat. 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