{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:45:51Z","timestamp":1791981951284,"version":"4.4.0"},"reference-count":0,"publisher":"Bentham Science Publishers Ltd.","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["DMB"],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"\n Introduction:<\/jats:title>\n Hepatic drug handling determines systemic exposure, yet the balance\nbetween tissue uptake, intracellular binding, and metabolic clearance is difficult to dissect in\nvivo. Cinacalcet hydrochloride (CINA), a calcimimetic used to manage secondary hyperparathyroidism,\nhas low oral bioavailability and is widely described as a high-extraction drug subject to\nextensive hepatic metabolism. Whether tissue sequestration rather than biotransformation underlies\nits rapid hepatic removal has not been tested directly in an intact ex vivo liver model.<\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n We investigated the hepatic clearance of cinacalcet hydrochloride (CINA) using the\nisolated perfused rat liver (IPRL) model. A validated high-performance liquid chromatography\n(HPLC) method was established to quantify CINA and its primary metabolite, M7, in both liver\ntissue and perfusate samples. To evaluate the influence of perfusate composition and protein\nbinding, experiments were conducted under single-pass perfusion modes, in the presence and\nabsence of bovine serum albumin (BSA).<\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n Dose recovery and mass balance analysis indicated that ~93% of the administered dose\nwas recovered: ~63% in liver tissue and ~29% in the outlet perfusate. No metabolites were detected\nin any sample, pointing to tissue uptake and retention as the dominant clearance mechanism.\nDrug loss to plastic perfusion tubing was substantial and was only partially offset by BSA.\nInclusion of BSA also shifted the apparent drug distribution between liver and perfusate.<\/jats:p>\n <\/jats:sec>\n \n Discussion:<\/jats:title>\n In the IPRL, hepatic tissue sequestration rather than metabolic conversion was the\ndominant clearance mechanism for CINA. Non-specific adsorption to plastic perfusion tubing\nand the protein content of the perfusion medium were important confounders that must be controlled\nin future ex vivo studies.<\/jats:p>\n <\/jats:sec>\n \n Conclusion:<\/jats:title>\n CINA was extensively retained in rat liver tissue with negligible in situ metabolism\nover 90 min of single-pass perfusion, raising the question of whether metabolic extraction truly\nexplains its low oral bioavailability in vivo.<\/jats:p>\n <\/jats:sec>","DOI":"10.2174\/0131173853473593260918121024","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:52:40Z","timestamp":1791978760000},"source":"Crossref","is-referenced-by-count":0,"title":["Revisiting Cinacalcet HCl Hepatic Disposition: Insights from Isolated Perfused Rat Liver"],"prefix":"10.2174","volume":"19","author":[{"given":"Katayoon","family":"Mireskandari","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran"},{"name":"Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmadreza","family":"Barazesh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa","family":"Rostamnezhad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Darabi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoda","family":"Lavasani","sequence":"additional","affiliation":[{"name":"Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammadreza","family":"Rouini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran"},{"name":"Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"965","container-title":["Drug Metabolism and Bioanalysis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.eurekaselect.com\/article\/download?doi=10.2174\/0131173853473593260918121024","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.eurekaselect.com\/259429\/article","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.eurekaselect.com\/article\/download?doi=10.2174\/0131173853473593260918121024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:52:45Z","timestamp":1791978765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.eurekaselect.com\/259429\/article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":0,"alternative-id":["LiveAll1"],"URL":"https:\/\/doi.org\/10.2174\/0131173853473593260918121024","relation":{},"ISSN":["3117-3853"],"issn-type":[{"value":"3117-3853","type":"print"}],"subject":[],"published":{"date-parts":[[2026,10,9]]}}}