{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T20:28:26Z","timestamp":1778617706375,"version":"3.51.4"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2021,4,2]],"date-time":"2021-04-02T00:00:00Z","timestamp":1617321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Based on the discovery that the estrogen synthase aromatase (CYP19A1) is abundantly expressed in high- grade gliomas, the aromatase inhibitor, letrozole is being investigated in pre-clinical models as a novel agent against this malignancy. Here, we investigated the systemic and brain pharmacokinetics of letrozole following single and steady state dosing in both male and female Sprague-Dawley rats. Furthermore, we employed physiologically-based pharmacokinetic (PBPK) modeling to gain quantitative insights into the blood-brain barrier penetration of this drug. Letrozole (4 mg\/kg) was administered intraperitoneally daily for 5 days (for males) and 11 days (for females) and intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Drug levels were measured using HPLC and non-compartmental analysis was conducted employing WinNonlin\u00ae. Simcyp animal simulator was used for conducting bottom-up PBPK approach incorporating the specified multi-compartment brain model. Overall, marked gender-specific differences in the systemic and brain pharmacokinetics of letrozole were observed. Letrozole clearance was much slower in female rats resulting in markedly higher plasma and brain drug concentrations. At steady state, the plasma AUC 0\u201324 was 103.0 and 24.8 \u03bcg*h\/ml and brain ECF AUC 0\u201312 was 24.0 and 4.8 \u03bcg*h\/ml in female and male rats, respectively. The PBPK model simulated brain concentration profiles were in close agreement with the observed profiles. While gender-specific differences in letrozole PK are not observed in the clinical setting, these findings will guide the dose optimization during pre-clinical investigations of this compound. The PBPK model will serve as an important clinical translational tool.<\/jats:p>","DOI":"10.1371\/journal.pone.0248579","type":"journal-article","created":{"date-parts":[[2021,4,2]],"date-time":"2021-04-02T17:30:52Z","timestamp":1617384652000},"page":"e0248579","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights"],"prefix":"10.1371","volume":"16","author":[{"given":"Priyanka","family":"Arora","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"Gudelsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3001-1603","authenticated-orcid":true,"given":"Pankaj B.","family":"Desai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,4,2]]},"reference":[{"issue":"12","key":"pone.0248579.ref001","first-page":"5171","article-title":"Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents","volume":"29","author":"G Minniti","year":"2009","journal-title":"Anticancer Res"},{"issue":"1","key":"pone.0248579.ref002","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s11060-013-1278-0","article-title":"Health-related quality of life and cognitive functioning in long-term anaplastic oligodendroglioma and oligoastrocytoma survivors","volume":"116","author":"EJ Habets","year":"2014","journal-title":"J Neurooncol"},{"issue":"3","key":"pone.0248579.ref003","doi-asserted-by":"crossref","first-page":"381","DOI":"10.4103\/0973-1482.119310","article-title":"Postoperative treatment of glioblastoma multiforme with radiation therapy plus concomitant and adjuvant temozolomide: A mono-institutional experience of 215 patients","volume":"9","author":"PK Julka","year":"2013","journal-title":"J Cancer Res Ther"},{"issue":"4","key":"pone.0248579.ref004","doi-asserted-by":"crossref","first-page":"e273","DOI":"10.3747\/co.22.2436","article-title":"Nonsurgical treatment of recurrent glioblastoma","volume":"22","author":"O Gallego","year":"2015","journal-title":"Curr Oncol"},{"issue":"4","key":"pone.0248579.ref005","doi-asserted-by":"crossref","first-page":"163","DOI":"10.4103\/2278-330X.175953","article-title":"Recurrent Glioblastoma: Where we stand","volume":"4","author":"S Roy","year":"2015","journal-title":"South Asian J Cancer"},{"issue":"1","key":"pone.0248579.ref006","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1602\/neurorx.2.1.3","article-title":"The blood-brain barrier: bottleneck in brain drug development","volume":"2","author":"WM Pardridge","year":"2005","journal-title":"NeuroRx"},{"issue":"Suppl 5","key":"pone.0248579.ref007","first-page":"v20","article-title":"ATPS-13 Aromatase expression in high grade gliomas: a potential new target for therapy","volume":"17","author":"N Dave","year":"2015","journal-title":"Neurooncol."},{"issue":"4","key":"pone.0248579.ref008","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1158\/1535-7163.MCT-14-0743","article-title":"Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas","volume":"14","author":"N Dave","year":"2015","journal-title":"Mol Cancer Ther."},{"issue":"2","key":"pone.0248579.ref009","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s11060-014-1509-z","article-title":"Aromatase and estrogen receptor alpha mRNA expression as prognostic biomarkers in patients with astrocytomas","volume":"119","author":"JM Due\u00f1as Jim\u00e9nez","year":"2014","journal-title":"J Neurooncol"},{"issue":"4","key":"pone.0248579.ref010","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1602\/neurorx.2.4.541","article-title":". Medicinal chemical properties of successful central nervous system drugs","volume":"2","author":"H Pajouhesh","year":"2005","journal-title":"NeuroRx."},{"issue":"9","key":"pone.0248579.ref011","doi-asserted-by":"crossref","first-page":"3309","DOI":"10.1002\/jps.23600","article-title":"Investigation of the effect of active efflux at the blood-brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system","volume":"102","author":"M Miyajima","year":"2013","journal-title":"J Pharm Sci"},{"issue":"2\u20133","key":"pone.0248579.ref012","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0169-409X(98)00085-4","article-title":"P-Glycoprotein, a gatekeeper in the blood-brain barrier","volume":"36","author":"AH Schinkel","year":"1999","journal-title":"Adv Drug Deliv Rev"},{"issue":"3","key":"pone.0248579.ref013","doi-asserted-by":"crossref","first-page":"E659","DOI":"10.1208\/aapsj070366","article-title":"In vivo microdialysis for PK and PD 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Liu","year":"2000","journal-title":"Acta Pharmacol Sin"},{"issue":"11","key":"pone.0248579.ref017","doi-asserted-by":"crossref","first-page":"4277","DOI":"10.1002\/jps.23266","article-title":"Development of a physiologically based pharmacokinetic model for the rat central nervous system and determination of an in vitro-in vivo scaling methodology for the blood-brain barrier permeability of two transporter substrates, morphine and oxycodone","volume":"101","author":"K Ball","year":"2012","journal-title":"J Pharm Sci"},{"issue":"1","key":"pone.0248579.ref018","doi-asserted-by":"crossref","first-page":"97","DOI":"10.3390\/pharmaceutics6010097","article-title":"Development of a physiologically-based pharmacokinetic model of the rat central nervous system","volume":"6","author":"RK Badhan","year":"2014","journal-title":"Pharmaceutics"},{"issue":"24","key":"pone.0248579.ref019","doi-asserted-by":"crossref","first-page":"7454","DOI":"10.1158\/1078-0432.CCR-17-0983","article-title":"Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients Using an IVIVE-PBPK Modeling Approach","volume":"23","author":"J Li","year":"2017","journal-title":"Clin Cancer Res"},{"issue":"3","key":"pone.0248579.ref020","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/bdd.2119","article-title":"Application of a physiologically-based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate","volume":"39","author":"MD Donovan","year":"2018","journal-title":"Biopharm Drug Dispos"},{"issue":"2","key":"pone.0248579.ref021","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0165-0270(80)90021-7","article-title":"AChE-stained horizontal sections of the rat brain in stereotaxic coordinates","volume":"3","author":"G Paxinos","year":"1980","journal-title":"J Neurosci Methods"},{"issue":"7","key":"pone.0248579.ref022","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1023\/A:1024406221962","article-title":"Modulation of nonspecific binding in ultrafiltration protein binding studies","volume":"20","author":"KJ Lee","year":"2003","journal-title":"Pharm Res."},{"issue":"6","key":"pone.0248579.ref023","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1002\/jps.20322","article-title":"Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases","volume":"94","author":"T Rodgers","year":"2005","journal-title":"J Pharm Sci."},{"issue":"6","key":"pone.0248579.ref024","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1002\/jps.20502","article-title":"Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals 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Tivnan","year":"2017","journal-title":"Oncotarget."},{"issue":"11","key":"pone.0248579.ref032","doi-asserted-by":"crossref","first-page":"795","DOI":"10.3109\/00498250903171395","article-title":"Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes","volume":"39","author":"K Murai","year":"2009","journal-title":"Xenobiotica"},{"issue":"Suppl 1","key":"pone.0248579.ref033","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s10549-007-9696-3","article-title":"The discovery and mechanism of action of letrozole","volume":"105","author":"AS Bhatnagar","year":"2007","journal-title":"Breast Cancer Res Treat"},{"issue":"11","key":"pone.0248579.ref034","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.2165\/00003495-200464110-00005","article-title":"Letrozole: a review of its use in postmenopausal women with breast cancer","volume":"64","author":"D Simpson","year":"2004","journal-title":"Drugs"},{"issue":"7","key":"pone.0248579.ref035","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1089\/omi.2013.0140","article-title":"High CYP2A6 enzyme activity as measured by a caffeine test and unique distribution of CYP2A6 variant alleles in Ethiopian population","volume":"18","author":"E Aklillu","year":"2014","journal-title":"OMICS"},{"issue":"3","key":"pone.0248579.ref036","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1124\/dmd.105.007716","article-title":"Inducibility of male-specific isoforms of cytochrome p450 by sex-dependent growth hormone profiles in hepatocyte cultures from male but not female rats","volume":"34","author":"C Thangavel","year":"2006","journal-title":"Drug Metab Dispos"},{"issue":"1\u20132","key":"pone.0248579.ref037","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0303-7207(00)00401-9","article-title":"Intrinsic signals in the sexually dimorphic circulating growth hormone profiles of the rat","volume":"173","author":"AK Agrawal","year":"2001","journal-title":"Mol Cell Endocrinol"},{"issue":"4","key":"pone.0248579.ref038","doi-asserted-by":"crossref","first-page":"290","DOI":"10.2174\/187231211798472557","article-title":"Gender effects on rat metabolism of AMG 900, an orally available small molecule aurora kinase inhibitor","volume":"5","author":"D Waldon","year":"2011","journal-title":"Drug Metab Lett."},{"issue":"Suppl","key":"pone.0248579.ref039","first-page":"117","article-title":"Pharmacokinetics of a new aromatase inhibitor CGS20267","volume":"18","author":"C Pfister","year":"1993","journal-title":"Eur J Drug Metab Pharmacokin"},{"issue":"5","key":"pone.0248579.ref040","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/bdd.273","article-title":"Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients","volume":"22","author":"CU Pfister","year":"2001","journal-title":"Biopharm Drug 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