{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:59:00Z","timestamp":1787878740275,"version":"build-2784847793"},"reference-count":90,"publisher":"Elsevier BV","issue":"6","license":[{"start":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T00:00:00Z","timestamp":1717200000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T00:00:00Z","timestamp":1717200000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["dmd.aspetjournals.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Drug Metabolism and Disposition"],"published-print":{"date-parts":[[2024,6]]},"DOI":"10.1124\/dmd.123.001435","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T18:50:26Z","timestamp":1706554226000},"page":"508-515","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":16,"title":["Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity"],"prefix":"10.1016","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6228-2136","authenticated-orcid":false,"given":"Jessica L.","family":"Beers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9388-9800","authenticated-orcid":false,"given":"Klarissa D.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1124\/dmd.123.001435_bib1","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.3390\/nu14102152","article-title":"Cannabidiol and cannabidiol metabolites: pharmacokinetics, interaction with food, and influence on liver function","volume":"14","author":"Abbotts","year":"2022","journal-title":"Nutrients"},{"key":"10.1124\/dmd.123.001435_bib2","doi-asserted-by":"crossref","first-page":"28857","DOI":"10.1074\/jbc.M011610200","article-title":"Human bile salt export pump promoter is transactivated by the farnesoid X receptor\/bile acid receptor","volume":"276","author":"Ananthanarayanan","year":"2001","journal-title":"J Biol Chem"},{"key":"10.1124\/dmd.123.001435_bib3","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1124\/dmd.108.022426","article-title":"Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDP-glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10","volume":"37","author":"Argikar","year":"2009","journal-title":"Drug Metab Dispos"},{"key":"10.1124\/dmd.123.001435_bib4","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1124\/dmd.122.001128","article-title":"A physiologically-based pharmacokinetic model for cannabidiol in healthy adults, hepatically-impaired adults, and children","volume":"51","author":"Bansal","year":"2023","journal-title":"Drug Metab Dispos"},{"key":"10.1124\/dmd.123.001435_bib5","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1124\/dmd.121.000734","article-title":"Comprehensive predictions of cytochrome P450 (P450)-mediated in vivo cannabinoid-drug interactions based on reversible and time-dependent P450 inhibition in human liver microsomes","volume":"50","author":"Bansal","year":"2022","journal-title":"Drug Metab Dispos"},{"key":"10.1124\/dmd.123.001435_bib6","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1021\/acsmedchemlett.3c00017","article-title":"Cytosolic enzymes generate cannabinoid metabolites 7-carboxycannabidiol and 11-nor-9-carboxytetrahydrocannabinol","volume":"14","author":"Beers","year":"2023","journal-title":"ACS Med Chem Lett"},{"key":"10.1124\/dmd.123.001435_bib7","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1124\/dmd.120.000350","article-title":"Cytochrome P450-catalyzed metabolism of cannabidiol to the active metabolite 7-hydroxy-cannabidiol","volume":"49","author":"Beers","year":"2021","journal-title":"Drug Metab Dispos"},{"key":"10.1124\/dmd.123.001435_bib8","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jhep.2010.11.006","article-title":"Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver","volume":"54","author":"Begriche","year":"2011","journal-title":"J Hepatol"},{"key":"10.1124\/dmd.123.001435_bib9","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/sj.bjp.0704327","article-title":"Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide","volume":"134","author":"Bisogno","year":"2001","journal-title":"Br J Pharmacol"},{"key":"10.1124\/dmd.123.001435_bib10","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/0006-291X(85)91014-9","article-title":"Inhibition of medium-chain fatty acid beta-oxidation in vitro by valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid","volume":"132","author":"Bjorge","year":"1985","journal-title":"Biochem Biophys Res Commun"},{"key":"10.1124\/dmd.123.001435_bib11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1528-1167.2012.03671.x","article-title":"Enzyme induction with antiepileptic drugs: cause for concern?","volume":"54","author":"Brodie","year":"2013","journal-title":"Epilepsia"},{"key":"10.1124\/dmd.123.001435_bib12","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1212\/WNL.46.2.465","article-title":"Valproic acid hepatic fatalities. III. U.S. experience since 1986","volume":"46","author":"Bryant","year":"1996","journal-title":"Neurology"},{"key":"10.1124\/dmd.123.001435_bib13","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.3390\/cells10051251","article-title":"Regulatory effects of cannabidiol on mitochondrial functions: a review","volume":"10","author":"Chan","year":"2021","journal-title":"Cells"},{"key":"10.1124\/dmd.123.001435_bib14","doi-asserted-by":"crossref","DOI":"10.1155\/2010\/479364","article-title":"Molecular and therapeutic potential and toxicity of valproic acid","volume":"2010","author":"Chateauvieux","year":"2010","journal-title":"J Biomed Biotechnol"},{"key":"10.1124\/dmd.123.001435_bib15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.cbi.2015.11.029","article-title":"In vitro model systems to investigate bile salt export pump (BSEP) activity and drug interactions: a review","volume":"255","author":"Cheng","year":"2016","journal-title":"Chem Biol Interact"},{"key":"10.1124\/dmd.123.001435_bib16","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1111\/j.1476-5381.2010.01166.x","article-title":"Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes","volume":"163","author":"De Petrocellis","year":"2011","journal-title":"Br J Pharmacol"},{"key":"10.1124\/dmd.123.001435_bib17","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1124\/jpet.107.134809","article-title":"Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8","volume":"325","author":"De Petrocellis","year":"2008","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1124\/dmd.123.001435_bib18","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1056\/NEJMoa1611618","article-title":"Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome","volume":"376","author":"Devinsky","year":"2017","journal-title":"N Engl J Med"},{"key":"10.1124\/dmd.123.001435_bib19","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1056\/NEJMoa1714631","article-title":"Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome","volume":"378","author":"Devinsky","year":"2018","journal-title":"N Engl J Med"},{"key":"10.1124\/dmd.123.001435_bib20","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1097\/00007691-198903000-00002","article-title":"Urinary excretion of valproate and some metabolites in chronically treated patients","volume":"11","author":"Dickinson","year":"1989","journal-title":"Ther Drug Monit"},{"key":"10.1124\/dmd.123.001435_bib21","doi-asserted-by":"crossref","first-page":"8711","DOI":"10.1074\/jbc.M114.618447","article-title":"Fatty acid-binding proteins (FABPs) are intracellular carriers for \u03949-tetrahydrocannabinol (THC) and cannabidiol (CBD)","volume":"290","author":"Elmes","year":"2015","journal-title":"J Biol Chem"},{"key":"10.1124\/dmd.123.001435_bib22","series-title":"Handbook of Cannabis","first-page":"3","article-title":"Constituents of Cannabis sativa","author":"ElSohly","year":"2014"},{"key":"10.1124\/dmd.123.001435_bib23","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1016\/S0006-2952(03)00076-5","article-title":"The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases","volume":"65","author":"Ethell","year":"2003","journal-title":"Biochem Pharmacol"},{"key":"10.1124\/dmd.123.001435_bib24","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.3390\/molecules24122256","article-title":"Paradoxical patterns of sinusoidal obstruction syndrome-like liver injury in aged female cd-1 mice triggered by cannabidiol-rich cannabis extract and acetaminophen co-administration","volume":"24","author":"Ewing","year":"2019","journal-title":"Molecules"},{"key":"10.1124\/dmd.123.001435_bib25","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.3390\/molecules24091694","article-title":"Hepatotoxicity of a cannabidiol-rich cannabis extract in the mouse model","volume":"24","author":"Ewing","year":"2019","journal-title":"Molecules"},{"key":"10.1124\/dmd.123.001435_bib26","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1007\/s40262-020-00931-w","article-title":"The interplay between liver first-pass effect and lymphatic absorption of cannabidiol and its implications for cannabidiol oral formulations","volume":"59","author":"Franco","year":"2020","journal-title":"Clin Pharmacokinet"},{"key":"10.1124\/dmd.123.001435_bib27","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/toxsci\/kfz154","article-title":"Novel mechanisms of valproate hepatotoxicity: impaired mrp2 trafficking and hepatocyte depolarization","volume":"171","author":"Fu","year":"2019","journal-title":"Toxicol Sci"},{"key":"10.1124\/dmd.123.001435_bib28","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1097\/FPC.0b013e32835ea0b2","article-title":"Valproic acid pathway: pharmacokinetics and pharmacodynamics","volume":"23","author":"Ghodke-Puranik","year":"2013","journal-title":"Pharmacogenet Genomics"},{"key":"10.1124\/dmd.123.001435_bib29","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1042\/bj3580147","article-title":"Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function","volume":"358","author":"Gincel","year":"2001","journal-title":"Biochem J"},{"key":"10.1124\/dmd.123.001435_bib30","doi-asserted-by":"crossref","DOI":"10.1016\/j.mcpro.2022.100262","article-title":"Multiomic analysis reveals disruption of cholesterol homeostasis by cannabidiol in human cell lines","volume":"21","author":"Guard","year":"2022","journal-title":"Mol Cell Proteomics"},{"key":"10.1124\/dmd.123.001435_bib31","doi-asserted-by":"crossref","first-page":"536","DOI":"10.2133\/dmpk.DMPK-11-NT-144","article-title":"Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy","volume":"27","author":"Guo","year":"2012","journal-title":"Drug Metab Pharmacokinet"},{"key":"10.1124\/dmd.123.001435_bib32","doi-asserted-by":"crossref","first-page":"303","DOI":"10.3109\/00498259009046849","article-title":"Metabolites of cannabidiol identified in human urine","volume":"20","author":"Harvey","year":"1990","journal-title":"Xenobiotica"},{"key":"10.1124\/dmd.123.001435_bib33","doi-asserted-by":"crossref","DOI":"10.1016\/j.taap.2023.116654","article-title":"Hepatic biotransformation of non-psychotropic phytocannabinoids and activity screening on cytochromes P450 and UDP-glucuronosyltransferases","volume":"476","author":"Havlasek","year":"2023","journal-title":"Toxicol Appl Pharmacol"},{"key":"10.1124\/dmd.123.001435_bib34","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1126\/science.1161302","article-title":"Solution structure of the integral human membrane protein VDAC-1 in detergent micelles","volume":"321","author":"Hiller","year":"2008","journal-title":"Science"},{"key":"10.1124\/dmd.123.001435_bib35","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s002329900235","article-title":"Regulation of metabolite flux through voltage-gating of VDAC channels","volume":"157","author":"Hodge","year":"1997","journal-title":"J Membr Biol"},{"key":"10.1124\/dmd.123.001435_bib36","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1093\/jat\/bkaa046","article-title":"Free and glucuronide urine cannabinoids after controlled smoked, vaporized and oral cannabis administration in frequent and occasional cannabis users","volume":"44","author":"Huestis","year":"2020","journal-title":"J Anal Toxicol"},{"key":"10.1124\/dmd.123.001435_bib37","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/s13311-015-0377-3","article-title":"Molecular targets of cannabidiol in neurological disorders","volume":"12","author":"Ibeas Bih","year":"2015","journal-title":"Neurotherapeutics"},{"key":"10.1124\/dmd.123.001435_bib38","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2021.802539","article-title":"The role of uptake and efflux transporters in the disposition of glucuronide and sulfate conjugates","volume":"12","author":"J\u00e4rvinen","year":"2022","journal-title":"Front Pharmacol"},{"key":"10.1124\/dmd.123.001435_bib39","doi-asserted-by":"crossref","DOI":"10.1038\/emm.2016.81","article-title":"Regulation and function of AMPK in physiology and diseases","volume":"48","author":"Jeon","year":"2016","journal-title":"Exp Mol Med"},{"key":"10.1124\/dmd.123.001435_bib40","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/s41419-019-2001-7","article-title":"Cannabidiol promotes apoptosis via regulation of XIAP\/Smac in gastric cancer","volume":"10","author":"Jeong","year":"2019","journal-title":"Cell Death Dis"},{"key":"10.1124\/dmd.123.001435_bib41","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.canlet.2019.01.011","article-title":"Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells","volume":"447","author":"Jeong","year":"2019","journal-title":"Cancer Lett"},{"key":"10.1124\/dmd.123.001435_bib42","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.lfs.2011.05.018","article-title":"Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes","volume":"89","author":"Jiang","year":"2011","journal-title":"Life Sci"},{"key":"10.1124\/dmd.123.001435_bib43","article-title":"Cannabidiol oil ingested as sublingual drops or within gelatin capsules shows similar pharmacokinetic profiles in healthy males","author":"Johnson","year":"2023","journal-title":"Cannabis Cannabinoid Res"},{"key":"10.1124\/dmd.123.001435_bib44","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrd1750","article-title":"Idiosyncratic drug hepatotoxicity","volume":"4","author":"Kaplowitz","year":"2005","journal-title":"Nat Rev Drug Discov"},{"key":"10.1124\/dmd.123.001435_bib45","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S0090-9556(25)07155-7","article-title":"Identification and characterization of the glutathione and N-acetylcysteine conjugates of (E)-2-propyl-2,4-pentadienoic acid, a toxic metabolite of valproic acid, in rats and humans","volume":"19","author":"Kassahun","year":"1991","journal-title":"Drug Metab Dispos"},{"key":"10.1124\/dmd.123.001435_bib46","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/0009-2797(94)90014-0","article-title":"Metabolic activation of unsaturated derivatives of valproic acid. Identification of novel glutathione adducts formed through coenzyme A-dependent and -independent processes","volume":"90","author":"Kassahun","year":"1994","journal-title":"Chem Biol Interact"},{"key":"10.1124\/dmd.123.001435_bib47","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1093\/toxsci\/kfl096","article-title":"Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1\/*1 genotype","volume":"94","author":"Kiang","year":"2006","journal-title":"Toxicol Sci"},{"key":"10.1124\/dmd.123.001435_bib48","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1002\/cpt.3004","article-title":"Assessing liver effects of cannabidiol and valproate alone and in combination using quantitative systems toxicology","volume":"114","author":"Lakhani","year":"2023","journal-title":"Clin Pharmacol Ther"},{"key":"10.1124\/dmd.123.001435_bib49","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1002\/iub.1682","article-title":"Human serum albumin: a modulator of cannabinoid drugs","volume":"69","author":"Leboffe","year":"2017","journal-title":"IUBMB Life"},{"key":"10.1124\/dmd.123.001435_bib50","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1055\/s-2003-42641","article-title":"Acute liver failure in the United States","volume":"23","author":"Lee","year":"2003","journal-title":"Semin Liver Dis"},{"key":"10.1124\/dmd.123.001435_bib51","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1021\/bi00216a012","article-title":"Mitochondrial metabolism of valproic acid","volume":"30","author":"Li","year":"1991","journal-title":"Biochemistry"},{"key":"10.1124\/dmd.123.001435_bib52","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/phar.2377","article-title":"Model-based analysis of cannabidiol dose-exposure relationship and bioavailability","volume":"40","author":"Lim","year":"2020","journal-title":"Pharmacotherapy"},{"key":"10.1124\/dmd.123.001435_bib53","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/jat.4409","article-title":"Physiologically based pharmacokinetic modeling and simulation of cannabinoids in human plasma and tissues","volume":"43","author":"Liu","year":"2023","journal-title":"J Appl Toxicol"},{"key":"10.1124\/dmd.123.001435_bib54","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1111\/imj.14415","article-title":"Model-based analysis on systemic availability of co-administered cannabinoids after controlled vaporised administration","volume":"50","author":"Liu","year":"2020","journal-title":"Intern Med J"},{"key":"10.1124\/dmd.123.001435_bib55","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1111\/joim.13627","article-title":"Cannabidiol-associated hepatotoxicity: a systematic review and meta-analysis","volume":"293","author":"Lo","year":"2023","journal-title":"J Intern Med"},{"key":"10.1124\/dmd.123.001435_bib56","article-title":"Sex differences in the pharmacokinetics of cannabidiol and metabolites following oral administration of a cannabidiol-dominant cannabis oil in healthy adults","author":"MacNair","year":"2023","journal-title":"Cannabis Cannabinoid Res"},{"key":"10.1124\/dmd.123.001435_bib57","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1007\/s00018-006-6156-x","article-title":"The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells","volume":"63","author":"Massi","year":"2006","journal-title":"Cell Mol Life Sci"},{"key":"10.1124\/dmd.123.001435_bib58","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1124\/dmd.109.026898","article-title":"Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids","volume":"37","author":"Mazur","year":"2009","journal-title":"Drug Metab Dispos"},{"key":"10.1124\/dmd.123.001435_bib59","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1124\/mol.106.023937","article-title":"Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression","volume":"70","author":"McKallip","year":"2006","journal-title":"Mol Pharmacol"},{"key":"10.1124\/dmd.123.001435_bib60","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1002\/cpdd.665","article-title":"A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects","volume":"8","author":"Morrison","year":"2019","journal-title":"Clin Pharmacol Drug Dev"},{"key":"10.1124\/dmd.123.001435_bib61","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.3390\/molecules26123573","article-title":"The effects of food on cannabidiol bioaccessibility","volume":"26","author":"Mozaffari","year":"2021","journal-title":"Molecules"},{"key":"10.1124\/dmd.123.001435_bib62","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1124\/dmd.121.000530","article-title":"Inhibition of UDP-glucuronosyltransferase enzymes by major cannabinoids and their metabolites","volume":"49","author":"Nasrin","year":"2021","journal-title":"Drug Metab Dispos"},{"key":"10.1124\/dmd.123.001435_bib63","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1124\/dmd.121.000442","article-title":"Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions","volume":"49","author":"Nasrin","year":"2021","journal-title":"Drug Metab Dispos"},{"key":"10.1124\/dmd.123.001435_bib64","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/bms.1200130206","article-title":"Single-dose kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous administration","volume":"13","author":"Ohlsson","year":"1986","journal-title":"Biomed Environ Mass Spectrom"},{"key":"10.1124\/dmd.123.001435_bib65","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/s41419-019-2024-0","article-title":"Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia","volume":"10","author":"Olivas-Aguirre","year":"2019","journal-title":"Cell Death Dis"},{"key":"10.1124\/dmd.123.001435_bib66","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s40263-020-00741-5","article-title":"Critical aspects affecting cannabidiol oral bioavailability and metabolic elimination, and related clinical implications","volume":"34","author":"Perucca","year":"2020","journal-title":"CNS Drugs"},{"key":"10.1124\/dmd.123.001435_bib67","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1021\/bi00010a026","article-title":"Role of sterols in the functional reconstitution of water-soluble mitochondrial porins from different organisms","volume":"34","author":"Popp","year":"1995","journal-title":"Biochemistry"},{"key":"10.1124\/dmd.123.001435_bib68","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1124\/dmd.121.000823","article-title":"Prediction of carboxylesterase 1-mediated in vivo drug interaction between methylphenidate and cannabinoids using static and physiologically based pharmacokinetic models","volume":"50","author":"Qian","year":"2022","journal-title":"Drug Metab Dispos"},{"key":"10.1124\/dmd.123.001435_bib69","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1007\/s00204-021-03114-z","article-title":"Metabolomic analysis to discriminate drug-induced liver injury (DILI) phenotypes","volume":"95","author":"Quint\u00e1s","year":"2021","journal-title":"Arch Toxicol"},{"key":"10.1124\/dmd.123.001435_bib70","doi-asserted-by":"crossref","DOI":"10.1038\/cddis.2013.471","article-title":"Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death","volume":"4","author":"Rimmerman","year":"2013","journal-title":"Cell Death Dis"},{"key":"10.1124\/dmd.123.001435_bib71","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s10571-011-9692-3","article-title":"The non-psychoactive plant cannabinoid, cannabidiol affects cholesterol metabolism-related genes in microglial cells","volume":"31","author":"Rimmerman","year":"2011","journal-title":"Cell Mol Neurobiol"},{"key":"10.1124\/dmd.123.001435_bib72","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/S0022-3565(24)37076-4","article-title":"Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid","volume":"283","author":"Sadeque","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1124\/dmd.123.001435_bib73","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1089\/can.2021.0202","article-title":"Population pharmacokinetics of oral-based administration of cannabidiol in healthy adults: implications for drug development","volume":"8","author":"Schultz","year":"2023","journal-title":"Cannabis Cannabinoid Res"},{"key":"10.1124\/dmd.123.001435_bib74","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.2217\/bmm.15.59","article-title":"Circulating mitochondrial biomarkers for drug-induced liver injury","volume":"9","author":"Shi","year":"2015","journal-title":"Biomarkers Med"},{"key":"10.1124\/dmd.123.001435_bib75","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1093\/jat\/bkab059","article-title":"Urinary pharmacokinetic profile of cannabidiol (CBD), \u03949-tetrahydrocannabinol (THC) and their metabolites following oral and vaporized CBD and vaporized CBD-dominant cannabis administration","volume":"46","author":"Sholler","year":"2022","journal-title":"J Anal Toxicol"},{"key":"10.1124\/dmd.123.001435_bib76","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/jat\/bkac042","article-title":"Urinary excretion profile of cannabinoid analytes following acute administration of oral and vaporized cannabis in infrequent cannabis users","volume":"46","author":"Sholler","year":"2022","journal-title":"J Anal Toxicol"},{"key":"10.1124\/dmd.123.001435_bib77","doi-asserted-by":"crossref","first-page":"164","DOI":"10.3389\/fonc.2012.00164","article-title":"VDAC1: from structure to cancer therapy","volume":"2","author":"Shoshan-Barmatz","year":"2012","journal-title":"Front Oncol"},{"key":"10.1124\/dmd.123.001435_bib78","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1158\/1535-7163.MCT-10-1100","article-title":"Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy","volume":"10","author":"Shrivastava","year":"2011","journal-title":"Mol Cancer Ther"},{"key":"10.1124\/dmd.123.001435_bib79","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3109\/00498254.2011.630110","article-title":"Why do metabolites circulate?","volume":"42","author":"Smith","year":"2012","journal-title":"Xenobiotica"},{"key":"10.1124\/dmd.123.001435_bib80","series-title":"Applied Biopharmaceutics and Pharmacokinetics","article-title":"Drug elimination and hepatic clearance","author":"Sun","year":"2016"},{"key":"10.1124\/dmd.123.001435_bib81","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s40263-018-0578-5","article-title":"A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects","volume":"32","author":"Taylor","year":"2018","journal-title":"CNS Drugs"},{"key":"10.1124\/dmd.123.001435_bib82","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1089\/can.2015.0012","article-title":"Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy","volume":"1","author":"Ujv\u00e1ry","year":"2016","journal-title":"Cannabis Cannabinoid Res"},{"key":"10.1124\/dmd.123.001435_bib83","series-title":"LiverTox: Clinical and Research Information on Drug-Induced Liver Injury","year":"2012"},{"key":"10.1124\/dmd.123.001435_bib84","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1007\/s12325-022-02345-5","article-title":"Examining the systemic bioavailability of cannabidiol and tetrahydrocannabinol from a novel transdermal delivery system in healthy adults: a single-arm, open-label, exploratory study","volume":"40","author":"Varadi","year":"2023","journal-title":"Adv Ther"},{"key":"10.1124\/dmd.123.001435_bib85","series-title":"The Pharmacology of Marihuana","first-page":"93","article-title":"Metabolism of cannabinoids in man","author":"Wall","year":"1976"},{"key":"10.1124\/dmd.123.001435_bib86","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/cts.12629","article-title":"The DILI-sim Initiative: insights into hepatotoxicity mechanisms and biomarker interpretation","volume":"12","author":"Watkins","year":"2019","journal-title":"Clin Transl Sci"},{"key":"10.1124\/dmd.123.001435_bib87","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1002\/hep.23151","article-title":"Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression","volume":"50","author":"Weerachayaphorn","year":"2009","journal-title":"Hepatology"},{"key":"10.1124\/dmd.123.001435_bib88","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.2042-7158.1980.tb12966.x","article-title":"Identification in human urine of delta 9-tetrahydrocannabinol-11-oic acid glucuronide: a tetrahydrocannabinol metabolite","volume":"32","author":"Williams","year":"1980","journal-title":"J Pharm Pharmacol"},{"key":"10.1124\/dmd.123.001435_bib89","article-title":"AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes","volume":"277","author":"Winder","year":"1999","journal-title":"Am J Physiol"},{"key":"10.1124\/dmd.123.001435_bib90","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1002\/psp4.12908","article-title":"Verifying in vitro-determined enzyme contributions to cannabidiol clearance for exposure predictions in human through physiologically-based pharmacokinetic modeling","volume":"12","author":"Yeung","year":"2023","journal-title":"CPT Pharmacometrics Syst Pharmacol"}],"container-title":["Drug Metabolism and Disposition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0090955624006895?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0090955624006895?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1124\/dmd.123.001435","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T08:50:48Z","timestamp":1739955048000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0090955624006895"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6]]},"references-count":90,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,6]]}},"alternative-id":["S0090955624006895"],"URL":"https:\/\/doi.org\/10.1124\/dmd.123.001435","relation":{},"ISSN":["0090-9556"],"issn-type":[{"value":"0090-9556","type":"print"}],"subject":[],"published":{"date-parts":[[2024,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity","name":"articletitle","label":"Article Title"},{"value":"Drug Metabolism and Disposition","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1124\/dmd.123.001435","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 by The American Society for Pharmacology and Experimental Therapeutics","name":"copyright","label":"Copyright"}]}}