{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T20:39:39Z","timestamp":1757623179422,"version":"3.44.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35-GM131800"],"award-info":[{"award-number":["R35-GM131800"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharm Res"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Purpose<\/jats:title>\n            <jats:p>Drugs can be found in erythrocytes (RBC) in accordance with their physicochemical and specific binding properties, but particularly high concentrations can be attained using an ex vivo hypotonic pre-swelling method. Pharmacokinetic (PK) methodology and characterization of <jats:italic>in vivo<\/jats:italic> data for RBC-loaded corticosteroid prodrugs was sought.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Three studies providing in vitro and <jats:italic>in vivo<\/jats:italic> assessments of the pharmacokinetics of steroid ester prodrugs loaded into RBC were found. A PK model involving three fractional input rates and two-compartment disposition was applied.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>After their sodium phosphate ester pro-drugs were loaded into RBC and dosed intravenously, dexamethasone (DEX) and betamethasone (BET) plasma concentrations were markedly prolonged with three phases in humans and animals. For DEX in humans, a PK model accounted for the typical biexponential disposition of the active steroid and for input of a large fraction (0.72) released within 1\u00a0h, a small fraction (0.27) released over several hours (<jats:italic>t<\/jats:italic>\n              <jats:sub>\n                <jats:italic>1\/2<\/jats:italic>\n              <\/jats:sub>\u2009=\u20095.5\u00a0h), and a very small fraction (0.008) released extremely slowly (<jats:italic>t<\/jats:italic>\n              <jats:sub>\n                <jats:italic>1\/2<\/jats:italic>\n              <\/jats:sub>\u2009=\u2009109\u00a0h). The DEX RBC concentrations were expected to remain far higher than plasma concentrations for this prolonged time. The PK model was also applied to DEX in rabbits and BET in rats with generally similar results and indicating full bioavailability.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The proposed PK methodology well characterized the input properties of RBC-loaded controlled-release formulations of corticosteroids in animal and humans in context of the flip-flop kinetics of the released drug. The model may be relevant to other types of RBC-loaded therapeutic agents.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s11095-025-03913-4","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T22:51:12Z","timestamp":1755211872000},"page":"1299-1306","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacokinetic Assessment of Drug Efflux from Erythrocytes Loaded with Corticosteroid Esters"],"prefix":"10.1007","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4027-0550","authenticated-orcid":false,"given":"William J.","family":"Jusko","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruihong","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"issue":"4","key":"3913_CR1","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1517\/17425241003610633","volume":"7","author":"VR Muzykantov","year":"2010","unstructured":"Muzykantov VR. Drug delivery by red blood cells: vascular carriers designed by mother nature. Expert Opin Drug Deliv. 2010;7(4):403\u201327.","journal-title":"Expert Opin Drug Deliv"},{"key":"3913_CR2","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12030276","author":"L Koleva","year":"2020","unstructured":"Koleva L, Bovt E, Ataullakhanov F, Sinauridze E. Erythrocytes as carriers: from drug delivery to biosensors. Pharmaceutics. 2020. https:\/\/doi.org\/10.3390\/pharmaceutics12030276.","journal-title":"Pharmaceutics"},{"key":"3913_CR3","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12050440","author":"PM Glassman","year":"2020","unstructured":"Glassman PM, Villa CH, Ukidve A, Zhao Z, Smith P, Mitragotri S, Russell AJ, Brenner JS, Muzykantov VR. Vascular drug delivery using carrier red blood cells: focus on RBC surface loading and pharmacokinetics. Pharmaceutics. 2020. https:\/\/doi.org\/10.3390\/pharmaceutics12050440.","journal-title":"Pharmaceutics"},{"key":"3913_CR4","doi-asserted-by":"publisher","first-page":"1308632","DOI":"10.3389\/fphys.2023.1308632","volume":"14","author":"S Biagiotti","year":"2023","unstructured":"Biagiotti S, Perla E, Magnani M. Drug transport by red blood cells. Front Physiol. 2023;14:1308632.","journal-title":"Front Physiol"},{"issue":"2","key":"3913_CR5","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1111\/cts.12724","volume":"13","author":"AH Jobe","year":"2020","unstructured":"Jobe AH, Milad MA, Peppard T, Jusko WJ. Pharmacokinetics and pharmacodynamics of intramuscular and oral betamethasone and dexamethasone in reproductive age women in India. Clin Transl Sci. 2020;13(2):391\u20139.","journal-title":"Clin Transl Sci"},{"issue":"2","key":"3913_CR6","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.tmrv.2017.09.001","volume":"32","author":"SA Coker","year":"2018","unstructured":"Coker SA, Szczepiorkowski ZM, Siegel AH, Ferrari A, Mambrini G, Anand R, Hartman RD, Benatti L, Dumont LJ. A study of the pharmacokinetic properties and the in vivo kinetics of erythrocytes loaded with dexamethasone sodium phosphate in healthy volunteers. Transfus Med Rev. 2018;32(2):102\u201310.","journal-title":"Transfus Med Rev"},{"issue":"9","key":"3913_CR7","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/S1474-4422(24)00220-5","volume":"23","author":"S Zielen","year":"2024","unstructured":"Zielen S, Crawford T, Benatti L, Magnani M, Kieslich M, Ryan M, Meyts I, Gulati S, Borgohain R, Yadav R, Pal P, Hegde A, Kumar S, Venkateswar A, Udani V, Vinayan KP, Nissenkorn A, Fazzi E, Leuzzi V, Stray-Pedersen A, Pietrucha B, Pascual SI, Gouider R, Koenig MK, Wu S, Perlman S, Thye D, Janhofer G, Horn B, Whitehouse W, Lederman H. Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2024;23(9):871\u201382.","journal-title":"Lancet Neurol"},{"issue":"2","key":"3913_CR8","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/s10928-020-09730-z","volume":"48","author":"W Krzyzanski","year":"2021","unstructured":"Krzyzanski W, Milad MA, Jobe AH, Peppard T, Bies RR, Jusko WJ. Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women. J Pharmacokinet Pharmacodyn. 2021;48(2):261\u201372.","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"3913_CR9","doi-asserted-by":"publisher","unstructured":"D\u2019Ascenzo M, Antonelli A, Chiarantini L, Mancini U, Magnani M. Red blood cells as a glucocorticoids delivery system. In: Sprandel U, Way JL editors. Erythrocytes as drug carriers in medicine. Boston, MA: Springer; 1997. https:\/\/doi.org\/10.1007\/978-1-4899-0044-9_11.","DOI":"10.1007\/978-1-4899-0044-9_11"},{"issue":"3","key":"3913_CR10","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/S0031-6997(24)01329-2","volume":"49","author":"PH Hinderling","year":"1997","unstructured":"Hinderling PH. Red blood cells: a neglected compartment in pharmacokinetics and pharmacodynamics. Pharmacol Rev. 1997;49(3):279\u201395.","journal-title":"Pharmacol Rev"},{"issue":"4","key":"3913_CR11","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1016\/S0090-9556(25)07474-4","volume":"21","author":"W Piekoszewski","year":"1993","unstructured":"Piekoszewski W, Chow FS, Jusko WJ. Disposition of tacrolimus (FK 506) in rabbits. role of red blood cell binding in hepatic clearance. Drug Metab Dispos. 1993;21(4):690\u20138.","journal-title":"Drug Metab Dispos"},{"issue":"5","key":"3913_CR12","doi-asserted-by":"publisher","first-page":"643","DOI":"10.4155\/tde.11.19","volume":"2","author":"JA Yanez","year":"2011","unstructured":"Yanez JA, Remsberg CM, Sayre CL, Forrest ML, Davies NM. Flip-flop pharmacokinetics\u2013delivering a reversal of disposition: challenges and opportunities during drug development. Ther Deliv. 2011;2(5):643\u201372.","journal-title":"Ther Deliv"},{"key":"3913_CR13","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics10040286","author":"X Zhang","year":"2018","unstructured":"Zhang X, Qiu M, Guo P, Lian Y, Xu E, Su J. Autologous red blood cell delivery of betamethasone phosphate sodium for long anti-inflammation. Pharmaceutics. 2018. https:\/\/doi.org\/10.3390\/pharmaceutics10040286.","journal-title":"Pharmaceutics"},{"issue":"12","key":"3913_CR14","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1248\/bpb1978.8.1032","volume":"8","author":"T Ogiso","year":"1985","unstructured":"Ogiso T, Iwaki M, Ohtori A. Encapsulation of dexamethasone in rabbit erythrocytes, the disposition in circulation and anti-inflammatory effect. J Pharmacobiodyn. 1985;8(12):1032\u201340.","journal-title":"J Pharmacobiodyn"},{"issue":"5","key":"3913_CR15","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1111\/j.1472-8206.1994.tb00822.x","volume":"8","author":"T Trenque","year":"1994","unstructured":"Trenque T, Lamiable D, Vistelle R, Millart H, Leperre A, Choisy H. Comparative pharmacokinetics of two diastereoisomers dexamethasone and betamethasone in plasma and cerebrospinal fluid in rabbits. Fundam Clin Pharmacol. 1994;8(5):430\u20136.","journal-title":"Fundam Clin Pharmacol"},{"issue":"2","key":"3913_CR16","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/S1570-0232(02)00271-4","volume":"776","author":"CS Tamvakopoulos","year":"2002","unstructured":"Tamvakopoulos CS, Neugebauer JM, Donnelly M, Griffin PR. Analysis of betamethasone in rat plasma using automated solid-phase extraction coupled with liquid chromatography-tandem mass spectrometry. Determination of plasma concentrations in rat following oral and intravenous administration. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;776(2):161\u20138.","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"3913_CR17","volume-title":"Adapt 5 User's Guide: Pharmacokinetics\/pharmacodynamic systems analysis software","author":"D D'Argenio","year":"2009","unstructured":"D\u2019Argenio D, Schumitzky A, Wang X. Adapt 5 User\u2019s Guide: Pharmacokinetics\/pharmacodynamic systems analysis software. BMSR: University of Southern California; 2009."},{"issue":"22","key":"3913_CR18","doi-asserted-by":"publisher","first-page":"3359","DOI":"10.1016\/0006-2952(83)90363-5","volume":"32","author":"E Pitt","year":"1983","unstructured":"Pitt E, Johnson CM, Lewis DA, Jenner DA, Offord RE. Encapsulation of drugs in intact erythrocytes: an intravenous delivery system. Biochem Pharmacol. 1983;32(22):3359\u201368.","journal-title":"Biochem Pharmacol"},{"issue":"2","key":"3913_CR19","first-page":"194","volume":"23","author":"GV Shavi","year":"2010","unstructured":"Shavi GV, Doijad RC, Deshpande PB, Manvi FV, Meka SR, Udupa N, Omprakash R, Dhirendra K. Erythrocytes as carrier for prednisolone: in vitro and in vivo evaluation. Pak J Pharm Sci. 2010;23(2):194\u2013200.","journal-title":"Pak J Pharm Sci"},{"issue":"10","key":"3913_CR20","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1002\/j.1552-4604.1996.tb04753.x","volume":"36","author":"GM Ferron","year":"1996","unstructured":"Ferron GM, Rochdi M, Jusko WJ, Scherrmann JM. Oral absorption characteristics and pharmacokinetics of colchicine in healthy volunteers after single and multiple doses. J Clin Pharmacol. 1996;36(10):874\u201383.","journal-title":"J Clin Pharmacol"},{"issue":"2","key":"3913_CR21","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1042\/BA20000087","volume":"33","author":"L Rossi","year":"2001","unstructured":"Rossi L, Serafini S, Cenerini L, Picardi F, Bigi L, Panzani I, Magnani M. Erythrocyte-mediated delivery of dexamethasone in patients with chronic obstructive pulmonary disease. Biotechnol Appl Biochem. 2001;33(2):85\u20139.","journal-title":"Biotechnol Appl Biochem"},{"issue":"9","key":"3913_CR22","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1124\/dmd.120.091017","volume":"48","author":"D Song","year":"2020","unstructured":"Song D, Sun L, DuBois DC, Almon RR, Meng S, Jusko WJ. Physiologically based pharmacokinetics of dexamethasone in rats. Drug Metab Dispos. 2020;48(9):811\u20138.","journal-title":"Drug Metab Dispos"},{"issue":"5","key":"3913_CR23","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1002\/bdd.2266","volume":"42","author":"D Song","year":"2021","unstructured":"Song D, Jusko WJ. Across-species meta-analysis of dexamethasone pharmacokinetics utilizing allometric and scaling modeling approaches. Biopharm Drug Dispos. 2021;42(5):191\u2013203.","journal-title":"Biopharm Drug Dispos"},{"issue":"6","key":"3913_CR24","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1023\/A:1018929824798","volume":"11","author":"EV Mishina","year":"1994","unstructured":"Mishina EV, Jusko WJ. Inhibition of rat splenocyte proliferation with methylprednisolone: in vivo effect of liposomal formulation. Pharm Res. 1994;11(6):848\u201354.","journal-title":"Pharm Res"},{"issue":"4","key":"3913_CR25","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1210\/endo-94-4-998","volume":"94","author":"PL Ballard","year":"1974","unstructured":"Ballard PL, Baxter JD, Higgins SJ, Rousseau GG, Tomkins GM. General presence of glucocorticoid receptors in mammalian tissues. Endocrinology. 1974;94(4):998\u20131002.","journal-title":"Endocrinology"},{"issue":"4","key":"3913_CR26","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/S0026-895X(25)10446-X","volume":"31","author":"MT Nakada","year":"1987","unstructured":"Nakada MT, Stadel JM, Poksay KS, Crooke ST. Glucocorticoid regulation of beta-adrenergic receptors in 3T3-L1 preadipocytes. Mol Pharmacol. 1987;31(4):377\u201384.","journal-title":"Mol Pharmacol"},{"issue":"2","key":"3913_CR27","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1124\/jpet.120.000191","volume":"375","author":"X Li","year":"2020","unstructured":"Li X, DuBois DC, Almon RR, Jusko WJ. Physiologically based pharmacokinetic modeling involving nonlinear plasma and tissue binding: application to prednisolone and prednisone in rats. J Pharmacol Exp Ther. 2020;375(2):385\u201396.","journal-title":"J Pharmacol Exp Ther"},{"issue":"7","key":"3913_CR28","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1124\/dmd.124.001711","volume":"52","author":"R Yu","year":"2024","unstructured":"Yu R, Jusko WJ. Physiologically based pharmacokinetic modeling: the reversible metabolism and tissue-specific partitioning of methylprednisolone and methylprednisone in rats. Drug Metab Dispos. 2024;52(7):662\u201372.","journal-title":"Drug Metab Dispos"},{"issue":"3","key":"3913_CR29","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1007\/s10928-021-09755-y","volume":"48","author":"W Krzyzanski","year":"2021","unstructured":"Krzyzanski W, Milad MA, Jobe AH, Peppard T, Bies RR, Jusko WJ. Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women. J Pharmacokinet Pharmacodyn. 2021;48(3):411\u201338.","journal-title":"J Pharmacokinet Pharmacodyn"}],"container-title":["Pharmaceutical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-025-03913-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11095-025-03913-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-025-03913-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T03:52:43Z","timestamp":1757389963000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11095-025-03913-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":29,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["3913"],"URL":"https:\/\/doi.org\/10.1007\/s11095-025-03913-4","relation":{},"ISSN":["0724-8741","1573-904X"],"issn-type":[{"type":"print","value":"0724-8741"},{"type":"electronic","value":"1573-904X"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"26 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"WJJ is a member of the scientific board of Quince Therapeutics Inc.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}