{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:38:01Z","timestamp":1783413481001,"version":"3.54.6"},"reference-count":56,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006108","name":"the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["2UL1TR001425-05A1"],"award-info":[{"award-number":["2UL1TR001425-05A1"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["1P30HD106451"],"award-info":[{"award-number":["1P30HD106451"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Maternal and Pediatric Precision in Therapeutics (MPRINT) Knowledge &amp; Research Coordination Center (KRCC) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)","award":["2UL1TR001425-05A1"],"award-info":[{"award-number":["2UL1TR001425-05A1"]}]},{"name":"Maternal and Pediatric Precision in Therapeutics (MPRINT) Knowledge &amp; Research Coordination Center (KRCC) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)","award":["1P30HD106451"],"award-info":[{"award-number":["1P30HD106451"]}]},{"name":"Rieveschl\/Parke-Davis Doctoral Candidacy Scholarship of the University of Cincinnati","award":["2UL1TR001425-05A1"],"award-info":[{"award-number":["2UL1TR001425-05A1"]}]},{"name":"Rieveschl\/Parke-Davis Doctoral Candidacy Scholarship of the University of Cincinnati","award":["1P30HD106451"],"award-info":[{"award-number":["1P30HD106451"]}]},{"name":"Japan Research Foundation for Clinical Pharmacology","award":["2UL1TR001425-05A1"],"award-info":[{"award-number":["2UL1TR001425-05A1"]}]},{"name":"Japan Research Foundation for Clinical Pharmacology","award":["1P30HD106451"],"award-info":[{"award-number":["1P30HD106451"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Buprenorphine readily crosses the placenta, and with greater prenatal exposure, neonatal opioid withdrawal syndrome (NOWS) likely grows more severe. Current dosing strategies can be further improved by tailoring doses to expected NOWS severity. To allow the conceptualization of fetal buprenorphine exposure, a maternal\u2013fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0). Buprenorphine transplacental passage was predicted from its physicochemical properties. The maternal\u2013fetal PBPK model integrated reduced transmucosal absorption driven by lower salivary pH and induced metabolism observed during pregnancy. Maternal pharmacokinetics was adequately predicted in the second trimester, third trimester, and postpartum period, with the simulated area under the curve from 0 to 12 h, apparent clearance, and peak concentration falling within the 1.25-fold prediction error range. Following post hoc adjustment of the likely degree of individual maternal sublingual absorption, umbilical cord blood concentrations at delivery (n = 21) were adequately predicted, with a geometric mean ratio between predicted and observed fetal concentrations of 1.15 and with 95.2% falling within the 2-fold prediction error range. The maternal\u2013fetal PBPK model developed in this study can be used to forecast fetal buprenorphine exposure and would be valuable to investigate its correlation to NOWS severity.<\/jats:p>","DOI":"10.3390\/pharmaceutics16030375","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T05:44:06Z","timestamp":1709876646000},"page":"375","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Forecasting Fetal Buprenorphine Exposure through Maternal\u2013Fetal Physiologically Based Pharmacokinetic Modeling"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8979-8797","authenticated-orcid":false,"given":"Matthijs W.","family":"van Hoogdalem","sequence":"first","affiliation":[{"name":"Division of Translational and Clinical Pharmacology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"},{"name":"James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0725-9237","authenticated-orcid":false,"given":"Khaled","family":"Abduljalil","sequence":"additional","affiliation":[{"name":"Certara UK Limited, Simcyp Division, Sheffield S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor N.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Certara UK Limited, Simcyp Division, Sheffield S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott L.","family":"Wexelblatt","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Perinatal Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"},{"name":"Center for Addiction Research, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry T.","family":"Akinbi","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Perinatal Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Vinks","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"},{"name":"Center for Addiction Research, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8471-9826","authenticated-orcid":false,"given":"Tomoyuki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"},{"name":"Center for Addiction Research, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"487","DOI":"10.2165\/00003088-200443080-00001","article-title":"Drug transfer and metabolism by the human placenta","volume":"43","author":"Syme","year":"2004","journal-title":"Clin. Pharmacokinet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2165\/00003088-199528030-00005","article-title":"Placental transfer of drugs administered to the mother","volume":"28","author":"Pacifici","year":"1995","journal-title":"Clin. Pharmacokinet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"674","DOI":"10.2174\/138920111795164057","article-title":"ATP-binding cassette efflux transporters in human placenta","volume":"12","author":"Ni","year":"2011","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0140-6736(62)91248-5","article-title":"Thalidomide and congenital abnormalities","volume":"1","author":"Speirs","year":"1962","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1001\/jama.2020.24991","article-title":"Neonatal Abstinence Syndrome and Maternal Opioid-Related Diagnoses in the US, 2010-2017","volume":"325","author":"Hirai","year":"2021","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1056\/NEJMoa1614835","article-title":"Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome","volume":"376","author":"Kraft","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1001\/jamapediatrics.2018.5044","article-title":"Pharmacological Treatments for Neonatal Abstinence Syndrome: A Systematic Review and Network Meta-analysis","volume":"173","author":"Disher","year":"2019","journal-title":"JAMA Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1097\/AOG.0000000000003231","article-title":"Medication-Assisted Treatment Use Among Pregnant Women with Opioid Use Disorder","volume":"133","author":"Krans","year":"2019","journal-title":"Obstet. Gynecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1038\/s41372-020-00886-7","article-title":"Toward the use of buprenorphine in infants for neonatal opioid withdrawal syndrome: Summary of an NIH workshop","volume":"41","author":"Simon","year":"2021","journal-title":"J. Perinatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/cpt.930","article-title":"Buprenorphine in Neonatal Abstinence Syndrome","volume":"103","author":"Kraft","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s40262-020-00939-2","article-title":"Physiologic Indirect Response Modeling to Describe Buprenorphine Pharmacodynamics in Newborns Treated for Neonatal Opioid Withdrawal Syndrome","volume":"60","author":"Mizuno","year":"2021","journal-title":"Clin. Pharmacokinet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1002\/cpt.2458","article-title":"Physiologically-Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome","volume":"111","author":"Johnson","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1002\/cpt.1064","article-title":"The Pharmacokinetics and Pharmacodynamics of Buprenorphine in Neonatal Abstinence Syndrome","volume":"103","author":"Moore","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e2020029074","DOI":"10.1542\/peds.2020-029074","article-title":"Neonatal Opioid Withdrawal Syndrome","volume":"146","author":"Patrick","year":"2020","journal-title":"Pediatrics"},{"key":"ref_15","first-page":"108045","article-title":"A review of pregnancy-induced changes in opioid pharmacokinetics, placental transfer, and fetal exposure: Towards fetomaternal physiologically-based pharmacokinetic modeling to improve the treatment of neonatal opioid withdrawal syndrome","volume":"234","author":"Wexelblatt","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1001\/jama.2021.7374","article-title":"Use of Medications for Treatment of Opioid Use Disorder Among US Medicaid Enrollees in 11 States, 2014\u20132018","volume":"326","author":"Donohue","year":"2021","journal-title":"JAMA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"880402","DOI":"10.3389\/fped.2022.880402","article-title":"Editorial: Exploring Maternal-Fetal Pharmacology Through PBPK Modeling Approaches","volume":"10","author":"Dallmann","year":"2022","journal-title":"Front. Pediatr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1124\/dmd.121.000711","article-title":"Prediction of Maternal and Fetoplacental Concentrations of Cefazolin, Cefuroxime, and Amoxicillin during Pregnancy Using Bottom-Up Physiologically Based Pharmacokinetic Models","volume":"50","author":"Abduljalil","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"van Hoogdalem, M.W., Johnson, T.N., Vinks, A.A., and Mizuno, T. (2022). Development and validation of a full physiologically-based pharmacokinetic model for sublingual buprenorphine that accounts for nonlinear bioavailability. Authorea.","DOI":"10.22541\/au.165479409.90378585\/v1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"365","DOI":"10.2165\/11597440-000000000-00000","article-title":"Anatomical, physiological and metabolic changes with gestational age during normal pregnancy: A database for parameters required in physiologically based pharmacokinetic modelling","volume":"51","author":"Abduljalil","year":"2012","journal-title":"Clin. Pharmacokinet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4377","DOI":"10.1021\/jm960073m","article-title":"Octanol-, chloroform-, and propylene glycol dipelargonat-water partitioning of morphine-6-glucuronide and other related opiates","volume":"39","author":"Avdeef","year":"1996","journal-title":"J. Med. Chem."},{"key":"ref_22","first-page":"1804","article-title":"Changes in salivary flow rate and pH in pregnancy","volume":"25","author":"Migliario","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1177\/009127009703700106","article-title":"Bioavailability of sublingual buprenorphine","volume":"37","author":"Mendelson","year":"1997","journal-title":"J. Clin. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1007\/s11095-006-9210-3","article-title":"Mechanistic approaches to volume of distribution predictions: Understanding the processes","volume":"24","author":"Rodgers","year":"2007","journal-title":"Pharm. Res."},{"key":"ref_25","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 and zwitterions","volume":"95","author":"Rodgers","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s10928-020-09711-2","article-title":"Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: Assessing the impact of the longitudinal changes in the activity of CYP1A2, CYP2D6 and CYP3A4 enzymes during pregnancy","volume":"47","author":"Abduljalil","year":"2020","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"676","DOI":"10.2174\/138920007782109733","article-title":"Prediction of intestinal first-pass drug metabolism","volume":"8","author":"Yang","year":"2007","journal-title":"Curr. Drug Metab."},{"key":"ref_28","unstructured":"NCBI (2022, April 20). National Center for Biotechnology Information: PubChem Compound Summary for CID 644073, Buprenorphine, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/644073."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1111\/bcp.13642","article-title":"Gestational changes in buprenorphine exposure: A physiologically-based pharmacokinetic analysis","volume":"84","author":"Zhang","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"64.e1","DOI":"10.1016\/j.ajog.2016.09.095","article-title":"Dose-adjusted plasma concentrations of sublingual buprenorphine are lower during than after pregnancy","volume":"216","author":"Bastian","year":"2017","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/j.1479-828X.2012.01424.x","article-title":"Buprenorphine exposure in infants of opioid-dependent mothers at birth","volume":"52","author":"Bartu","year":"2012","journal-title":"Aust. N. Z. J. Obstet. Gynaecol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e385","DOI":"10.1055\/s-0036-1593993","article-title":"Naloxone and Metabolites Quantification in Cord Blood of Prenatally Exposed Newborns and Correlations with Maternal Concentrations","volume":"6","author":"Wiegand","year":"2016","journal-title":"AJP Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1111\/j.1365-2125.1982.tb01434.x","article-title":"Sublingual buprenorphine used postoperatively: Ten hour plasma drug concentration analysis","volume":"13","author":"Bullingham","year":"1982","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0376-8716(03)00188-1","article-title":"Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid na\u00efve healthy male volunteers under a naltrexone block","volume":"72","author":"McAleer","year":"2003","journal-title":"Drug Alcohol. Depend."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1080\/14767050802610328","article-title":"Effect of plasma proteins on buprenorphine transfer across dually perfused placental lobule","volume":"22","author":"Nanovskaya","year":"2009","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1124\/jpet.300.1.26","article-title":"Transplacental transfer and metabolism of buprenorphine","volume":"300","author":"Nanovskaya","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1017\/S1461145709990848","article-title":"Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)","volume":"13","author":"Tournier","year":"2010","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1124\/dmd.112.046276","article-title":"Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone","volume":"41","author":"Choi","year":"2013","journal-title":"Drug Metab. Dispos."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1515\/jpme.1990.18.6.479","article-title":"Maternal kinetics of morphine during labour","volume":"18","author":"Gerdin","year":"1990","journal-title":"J. Perinat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1093\/infdis\/163.2.226","article-title":"Pharmacokinetic disposition of zidovudine during pregnancy","volume":"163","author":"Watts","year":"1991","journal-title":"J. Infect. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/cpt197824152","article-title":"Kinetics of intravenous and intramuscular morphine","volume":"24","author":"Stanski","year":"1978","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1124\/dmd.31.5.580","article-title":"Utility of hepatocytes in predicting drug metabolism: Comparison of hepatic intrinsic clearance in rats and humans in vivo and in vitro","volume":"31","author":"Naritomi","year":"2003","journal-title":"Drug Metab. Dispos."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/PL00007495","article-title":"Assessment of the hepatic arterial and portal venous blood flows during pregnancy with Doppler ultrasonography","volume":"266","author":"Nakai","year":"2002","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1124\/mol.107.043851","article-title":"Effect of pregnancy on cytochrome P450 3a and P-glycoprotein expression and activity in the mouse: Mechanisms, tissue specificity, and time course","volume":"74","author":"Zhang","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1124\/jpet.118.254219","article-title":"In Utero Exposure to Norbuprenorphine, a Major Metabolite of Buprenorphine, Induces Fetal Opioid Dependence and Leads to Neonatal Opioid Withdrawal Syndrome","volume":"370","author":"Griffin","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/0003-9969(88)90022-2","article-title":"Pregnancy-related changes in human whole saliva","volume":"33","author":"Laine","year":"1988","journal-title":"Arch. Oral. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/clpt.1980.219","article-title":"Buprenorphine kinetics","volume":"28","author":"Bullingham","year":"1980","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"661","DOI":"10.2165\/00003088-200544070-00001","article-title":"Buprenorphine: Clinical pharmacokinetics in the treatment of opioid dependence","volume":"44","author":"Elkader","year":"2005","journal-title":"Clin. Pharmacokinet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"569","DOI":"10.2133\/dmpk.16.569","article-title":"Pharmacokinetics of buprenorphine hydrochloride (BN\u2022HCl) (1): Absorption, distribution, metabolism and excretion after percutaneous (TSN-09: BN\u00b7HCl containing tape application) or subcutaneous administration of BN\u00b7HCl in rats","volume":"16","author":"Takahashi","year":"2001","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4928","DOI":"10.1002\/jps.21770","article-title":"Differential involvement of P-glycoprotein (ABCB1) in permeability, tissue distribution, and antinociceptive activity of methadone, buprenorphine, and diprenorphine: In vitro and in vivo evaluation","volume":"98","author":"Hassan","year":"2009","journal-title":"J. Pharm. Sci."},{"key":"ref_51","first-page":"3","article-title":"Pharmacokinetics of [3H]-buprenorphine in the rat","volume":"64","author":"Holland","year":"1989","journal-title":"Res. Commun. Chem. Pathol. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1124\/dmd.105.003681","article-title":"In vitro metabolism study of buprenorphine: Evidence for new metabolic pathways","volume":"33","author":"Picard","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2174\/187231209788654117","article-title":"Glucuronidation of buprenorphine and norbuprenorphine by human liver microsomes and UDP-glucuronosyltransferases","volume":"3","author":"Chang","year":"2009","journal-title":"Drug Metab. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1007\/s11095-008-9823-9","article-title":"Relative importance of intestinal and hepatic glucuronidation-impact on the prediction of drug clearance","volume":"26","author":"Cubitt","year":"2009","journal-title":"Pharm. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1124\/dmd.115.068643","article-title":"How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach","volume":"44","author":"Johnson","year":"2016","journal-title":"Drug Metab. Dispos."},{"key":"ref_56","unstructured":"Reckitt & Colman Pharmaceuticals, Inc. (2000). NDA: 20-733 Suboxone\u00ae Sublingual Tablets\u2014Clinical Pharmacology\/Biopharmaceutics Review, Reckitt & Colman Pharmaceuticals, Inc."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/3\/375\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:10:51Z","timestamp":1760105451000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/3\/375"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,8]]},"references-count":56,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["pharmaceutics16030375"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16030375","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,8]]}}}