{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:01:09Z","timestamp":1781632869453,"version":"3.54.5"},"reference-count":23,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Evaluation Institute of Industrial Technology (KEIT)","award":["20008840"],"award-info":[{"award-number":["20008840"]}]},{"name":"Korea Evaluation Institute of Industrial Technology (KEIT)","award":["2022R1A2C1004714"],"award-info":[{"award-number":["2022R1A2C1004714"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["20008840"],"award-info":[{"award-number":["20008840"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["2022R1A2C1004714"],"award-info":[{"award-number":["2022R1A2C1004714"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Leuprolide is a synthetic nonapeptide drug (pyroGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt) that acts as a gonadotropin-releasing hormone agonist. The continuous administration of therapeutic doses of leuprolide inhibits gonadotropin secretion, which is used in androgen-deprivation therapy for the treatment of advanced prostate cancer, central precocious puberty, endometriosis, uterine fibroids, and other sex-hormone-related conditions. To improve the pharmacokinetic properties of peptide drugs, a fatty acid was conjugated with leuprolide for long-term action. In this study, we developed a simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS\/MS) method for the simultaneous determination of leuprolide and leuprolide\u2013oleic acid conjugate (LOC) levels. The developed method was validated in terms of linearity, precision, accuracy, recovery, matrix effect, and stability according to the US Food and Drug Administration guidelines, and the parameters were within acceptable limits. Subsequently, the pharmacokinetics of leuprolide and LOCs were evaluated. In vivo rat subcutaneous studies revealed that conjugation with fatty acids significantly altered the pharmacokinetics of leuprolide. After the subcutaneous administration of fatty-acid-conjugated leuprolide, the mean absorption time and half-life were prolonged. To the best of our knowledge, this is the first study showing the effects of fatty acid conjugates on the pharmacokinetics of leuprolide using a newly developed UPLC-MS\/MS method for the simultaneous quantification of leuprolide and LOCs.<\/jats:p>","DOI":"10.3390\/molecules27248716","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T03:23:49Z","timestamp":1670556229000},"page":"8716","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Determination of Leuprolide\u2013Fatty Acid Conjugate in Rat Plasma Using LC-MS\/MS and Its Pharmacokinetics after Subcutaneous Administration in Rats"],"prefix":"10.3390","volume":"27","author":[{"given":"Gi-Sang","family":"Seong","sequence":"first","affiliation":[{"name":"College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Wook","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Young","family":"Cho","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kye Wan","family":"Lee","sequence":"additional","affiliation":[{"name":"Dongkook Pharmaceutical Co., Ltd., Seoul 06072, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0922-3289","authenticated-orcid":false,"given":"Beom-Jin","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea"},{"name":"Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0997-5723","authenticated-orcid":false,"given":"In-Soo","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1292-5508","authenticated-orcid":false,"given":"Hyo-Eon","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea"},{"name":"Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"ref_1","first-page":"29","article-title":"The molecular mechanism of action of gonadotropin releasing hormone (GnRH) in the pituitary","volume":"43","author":"Conn","year":"1987","journal-title":"Recent. 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