{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T13:21:54Z","timestamp":1764595314583,"version":"3.46.0"},"reference-count":18,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T00:00:00Z","timestamp":1764460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National College Students Innovation and Entrepreneurship Training Program Project","award":["202311810009"],"award-info":[{"award-number":["202311810009"]}]},{"name":"Hainan Provincial Natural Science Foundation of China","award":["825QN329"],"award-info":[{"award-number":["825QN329"]}]},{"name":"Academic Enhancement Support Program of Hainan Medical University","award":["XSTS2025190"],"award-info":[{"award-number":["XSTS2025190"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Cyclin-dependent kinase 4\/6 (CDK4\/6) represents one of the clinically validated and therapeutically effective anticancer targets. Methods: This study established a rapid and sensitive HPLC-MS\/MS method for quantitative determination of XMD12, a novel CDK4\/6 inhibitor developed in our laboratory, in various rat biological matrices including plasma, tissue homogenates, urine and feces. The experimental design comprised three distinct phases: pharmacokinetic evaluation in 10 Sprague-Dawley SD rats (5 receiving 2.0 mg\/kg intravenous injection via tail vein and 5 administered 10.0 mg\/kg by gastric gavage); tissue distribution assessment in 25 SD rats following a single 20 mg\/kg gastric gavage; and an excretion study in 5 SD rats following a single 20 mg\/kg gastric gavage. Biological samples were systematically collected post-dosing and analyzed using a validated LC-MS\/MS method. Results: Key pharmacokinetic characteristics revealed (1) delayed absorption with significantly limited systemic exposure following gastric gavage; (2) preferential hepatic accumulation post-intestinal absorption followed by rapid clearance through metabolic\/biliary pathways with multi-organ collaborative elimination; and (3) time-dependent cumulative excretion predominantly via feces, suggesting final clearance through biliary-mediated intestinal elimination of metabolites. Conclusions: These findings demonstrate XMD12\u2019s dynamic disposition pattern characterized by \u201crestricted absorption\u2013hepatic metabolic priority\u2013multi-tissue collaborative clearance\u201d in vivo. This comprehensive investigation provides crucial pharmacokinetic parameters and excretion profiles for the anticancer lead compound XMD12, offering valuable insights for pharmacodynamic and toxicological evaluations while establishing a foundation for structural optimization and derivative screening of lead compounds.<\/jats:p>","DOI":"10.3390\/pharmaceutics17121545","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T13:03:02Z","timestamp":1764594182000},"page":"1545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Absorption, Distribution, Excretion, and In Vitro Hepatic Microsomal Metabolism of the Novel CDK Compound XMD12 in Sprague-Dawley Rats"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7735-2969","authenticated-orcid":false,"given":"Xue-Hai","family":"Zheng","sequence":"first","affiliation":[{"name":"School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571159, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Chun","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571159, China"},{"name":"Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Haikou 571199, China"},{"name":"Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China"},{"name":"Haikou Key Laboratory of Li Nationality Medicine, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0298-7294","authenticated-orcid":false,"given":"Yong-Hui","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571159, China"},{"name":"Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Haikou 571199, China"},{"name":"Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China"},{"name":"Haikou Key Laboratory of Li Nationality Medicine, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Xia","family":"He","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571159, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei-Xiong","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571159, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei-Fei","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571159, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-Yu","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571159, China"},{"name":"Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Haikou 571199, China"},{"name":"Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China"},{"name":"Haikou Key Laboratory of Li Nationality Medicine, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8629-8463","authenticated-orcid":false,"given":"Yin-Feng","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571159, China"},{"name":"Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Haikou 571199, China"},{"name":"Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China"},{"name":"Haikou Key Laboratory of Li Nationality Medicine, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nrc2602","article-title":"Cell cycle, CDKs and cancer: A changing paradigm","volume":"9","author":"Malumbres","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1056\/NEJMoa1609709","article-title":"Ribociclib as first-line therapy for HR-positive, advanced breast cancer","volume":"375","author":"Hortobagyi","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1056\/NEJMoa1607303","article-title":"Palbociclib and letrozole in advanced breast cancer","volume":"375","author":"Finn","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1200\/JCO.2017.73.7585","article-title":"MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+\/HER2\u2212 advanced breast cancer who had progressed while receiving endocrine therapy","volume":"35","author":"Sledge","year":"2017","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Piezzo, M., Chiodini, P., Riemma, M., Cocco, S., Caputo, R., Cianniello, D., Di Gioia, G., Di Lauro, V., Rella, F.D., and Fusco, G. (2020). Progression-free survival and overall survival of CDK 4\/6 inhibitors plus endocrine therapy in metastatic breast cancer: A systematic review and meta-analysis. Int. J. Mol. Sci., 21.","DOI":"10.21203\/rs.2.24219\/v1"},{"key":"ref_6","unstructured":"(2025, October 25). FDA Approves Abemaciclib for HR-Positive, HER2-Negative Breast Cancer. FDA, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-abemaciclib-hr-positive-her2-negative-breast-cancer."},{"key":"ref_7","unstructured":"(2025, October 25). Ribociclib (kisqali). FDA, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/ribociclib-kisqali."},{"key":"ref_8","unstructured":"(2025, October 25). Palbociclib (IBRANCE). FDA, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/palbociclib-ibrance."},{"key":"ref_9","first-page":"77","article-title":"Computational optimization and in silico analysis for the discovery of new HER2 and CDK4\/6 drug candidates for breast cancer","volume":"26","author":"Elmallah","year":"2025","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1002\/med.1015","article-title":"Pharmacokinetics and its role in small molecule drug discovery research","volume":"21","author":"Jang","year":"2001","journal-title":"Med. Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dhakne, P., Sahu, A.K., Sharma, M.K., and Sengupta, P. (2020). Simultaneous quantification of abemaciclib and letrozole in rat plasma: Method development, validation and pharmacokinetic application. Biomed. Chromatogr., 34.","DOI":"10.1002\/bmc.4825"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1080\/17425255.2018.1514720","article-title":"Pharmacokinetic drug evaluation of palbociclib for the treatment of breast cancer","volume":"14","author":"Maiello","year":"2018","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e4984","DOI":"10.1002\/jms.4984","article-title":"Simple and rapid quantification of ribociclib in rat plasma by protein precipitation and LC-MS\/MS: An application to pharmacokinetics of ribociclib nanoparticles in rats","volume":"58","author":"Alshogran","year":"2023","journal-title":"J. Mass Spectrom."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s40265-020-01461-2","article-title":"Inhibiting CDK4\/6 in breast cancer with palbociclib, ribociclib, and abemaciclib: Similarities and differences","volume":"81","author":"Braal","year":"2021","journal-title":"Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1007\/s40262-020-00930-x","article-title":"Clinical pharmacokinetics and pharmacodynamics of the cyclin-dependent kinase 4 and 6 inhibitors palbociclib, ribociclib, and abemaciclib","volume":"59","author":"Groenland","year":"2020","journal-title":"Clin. Pharmacokinet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1002\/cpdd.853","article-title":"Evaluation of absolute oral bioavailability and bioequivalence of ribociclib, a cyclin-dependent kinase 4\/6 inhibitor, in healthy subjects","volume":"9","author":"Ji","year":"2020","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, Y., Li, Y., Liu, D., Zheng, D., Li, X., Li, C., Huang, C., Wang, Y., Wang, X., and Li, Q. (2023). A potential anti-glioblastoma compound LH20 induces apoptosis and arrest of human glioblastoma cells via CDK4\/6 inhibition. Molecules, 28.","DOI":"10.3390\/molecules28135047"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"67","DOI":"10.17145\/jab.18.010","article-title":"Bioanalytical method development and validation: From the USFDA 2001 to the USFDA 2018 guidance for industry","volume":"4","author":"Meesters","year":"2018","journal-title":"J. Appl. 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