{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T18:06:23Z","timestamp":1768586783417,"version":"3.49.0"},"reference-count":28,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T00:00:00Z","timestamp":1731110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["P01DA032507"],"award-info":[{"award-number":["P01DA032507"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>\u03949-Tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis which is being increasingly consumed by pregnant people. In humans, THC is sequentially metabolized in the liver to its circulating metabolites 11-hydroxy-THC (11-OH-THC, psychoactive) and 11-nor-9-carboxy-THC (THC-COOH, non-psychoactive). Human and macaque data show that fetal exposure to THC is considerably lower than the corresponding maternal exposure. Through perfused human placenta studies, we showed that this is due to the active efflux of THC (fetal-to-maternal) by a placental transporter(s) other than P-glycoprotein or breast cancer resistance protein. The identity of this placental transporter(s) as well as whether THC or its metabolites are substrates or inhibitors of hepatic solute carrier transporters is unknown. Therefore, we investigated whether 5 \u03bcM THC, 0.3 \u03bcM 11-OH-THC, and 2.5 \u03bcM THC-COOH are substrates and\/or inhibitors of placental or hepatic solute carrier transporters at their pharmacologically relevant concentrations. Using HEK cells overexpressing human OATP1B1, OATP1B3, OATP2B1, OCT1, OCT3, OAT2, OAT4, or NTCP, and prototypic substrates\/inhibitors of these transporters, we found that THC and THC-COOH were substrates but not inhibitors of OCT1. THC-COOH was a weak substrate of OCT3 and a weak inhibitor of OAT4. THC, 11-OH-THC, and THC-COOH were found not to be substrates\/inhibitors of the remaining transporters investigated.<\/jats:p>","DOI":"10.3390\/ijms252212036","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T03:52:07Z","timestamp":1731297127000},"page":"12036","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Are \u03949-Tetrahydrocannabinol and Its Major Metabolites Substrates or Inhibitors of Placental or Human Hepatic Drug Solute-Carrier Transporters?"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9294-7204","authenticated-orcid":false,"given":"Xin","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsuzsanna","family":"G\u00e1borik","sequence":"additional","affiliation":[{"name":"SOLVO Biotechnology, Charles River Laboratories Hungary, Irinyi J\u00f3zsef u. 4-20, 1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingcheng","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4820-8455","authenticated-orcid":false,"given":"Jashvant D.","family":"Unadkat","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1001\/jama.2019.7982","article-title":"Self-Reported Medical and Nonmedical Cannabis Use Among Pregnant Women in the United States","volume":"322","author":"Volkow","year":"2019","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1001\/jama.2021.16328","article-title":"Rates of Prenatal Cannabis Use Among Pregnant Women Before and During the COVID-19 Pandemic","volume":"326","author":"Ray","year":"2021","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.pharmthera.2017.08.014","article-title":"Cannabis Use during Pregnancy: Pharmacokinetics and Effects on Child Development","volume":"182","author":"Grant","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e20181889","DOI":"10.1542\/peds.2018-1889","article-title":"Marijuana Use During Pregnancy and Breastfeeding: Implications for Neonatal and Childhood Outcomes","volume":"142","author":"Ryan","year":"2018","journal-title":"Pediatrics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0041-008X(87)90338-3","article-title":"Fetal Disposition of Delta 9-Tetrahydrocannabinol (THC) during Late Pregnancy in the Rhesus Monkey","volume":"90","author":"Bailey","year":"1987","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1002\/cpt.2964","article-title":"Understanding the Mechanism and Extent of Transplacental Transfer of (\u2212)-\u2206(9)-Tetrahydrocannabinol (THC) in the Perfused Human Placenta to Predict In Vivo Fetal THC Exposure","volume":"114","author":"Kumar","year":"2023","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1080\/17425255.2018.1499726","article-title":"An Update on Expression and Function of P-Gp\/ABCB1 and BCRP\/ABCG2 in the Placenta and Fetus","volume":"14","author":"Han","year":"2018","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1369-1600.2008.00096.x","article-title":"Disposition of \u03949 Tetrahydrocannabinol in CF1 Mice Deficient in Mdr1a P-Glycoprotein","volume":"13","author":"Benyamina","year":"2008","journal-title":"Addict. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1124\/dmd.121.000505","article-title":"Tetrahydrocannabinol and Its Major Metabolites Are Not (or Are Poor) Substrates or Inhibitors of Human P-Glycoprotein [ATP-Binding Cassette (ABC) B1] and Breast Cancer Resistance Protein (ABCG2)","volume":"49","author":"Chen","year":"2021","journal-title":"Drug Metab. Dispos."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1124\/dmd.122.001110","article-title":"Maternal and Fetal Exposure to (\u2212)-\u03949-Tetrahydrocannabinol and Its Major Metabolites in Pregnant Mice Is Differentially Impacted by P-Glycoprotein and Breast Cancer Resistance Protein","volume":"51","author":"Chen","year":"2023","journal-title":"Drug Metab. Dispos."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yamashita, M., and Markert, U.R. (2021). Overview of Drug Transporters in Human Placenta. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313149"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1124\/dmd.120.000067","article-title":"Gestational Age-Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics","volume":"48","author":"Anoshchenko","year":"2020","journal-title":"Drug Metab. Dispos."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.lfs.2006.12.032","article-title":"Cytochrome P450 Enzymes Involved in the Metabolism of Tetrahydrocannabinols and Cannabinol by Human Hepatic Microsomes","volume":"80","author":"Watanabe","year":"2007","journal-title":"Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1124\/dmd.119.086470","article-title":"Quantifying Hepatic Enzyme Kinetics of (\u2212)-\u22069-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, 11-OH-THC, through In Vitro Modeling","volume":"47","author":"Unadkat","year":"2019","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_15","first-page":"371","article-title":"Metabolism and Disposition of \u03949-Tetrahydrocannabinol in Man","volume":"23","author":"Lemberger","year":"1971","journal-title":"Pharmacol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3727\/105221619X15469715711907","article-title":"Blood-Bile Barrier: Morphology, Regulation, and Pathophysiology","volume":"19","author":"Monga","year":"2019","journal-title":"Gene Expr."},{"key":"ref_17","unstructured":"Kumar, A.R. (2023). Quantification and Prediction of Human Fetal (\u2212)-\u03949-Tetrahydrocannabinol (THC)\/11-OH-THC Exposure to Inform Neurodevelopmental Toxicity of Cannabis. [Ph.D. Thesis, University of Washington]."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e12013","DOI":"10.14814\/phy2.12013","article-title":"Paracellular Route Is the Major Urate Transport Pathway across the Blood-Placental Barrier","volume":"2","author":"Uehara","year":"2014","journal-title":"Physiol. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1152\/ajpregu.2000.279.4.R1495","article-title":"Expression of Members of the Multidrug Resistance Protein Family in Human Term Placenta","volume":"279","author":"Serrano","year":"2000","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1093\/jnci\/92.16.1295","article-title":"A Family of Drug Transporters: The Multidrug Resistance-Associated Proteins","volume":"92","author":"Borst","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1124\/mol.118.112482","article-title":"Organic Cation Transporter 3 Facilitates Fetal Exposure to Metformin during Pregnancy","volume":"94","author":"Lee","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Samodelov, S.L., Kullak-Ublick, G.A., Gai, Z., and Visentin, M. (2020). Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217890"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1002\/cbdv.200790152","article-title":"Human Cannabinoid Pharmacokinetics","volume":"4","author":"Huestis","year":"2007","journal-title":"Chem. Biodivers."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jchromb.2003.09.022","article-title":"Validated Method for the Simultaneous Determination of \u03949-Tetrahydrocannabinol (THC), 11-Hydroxy-THC and 11-nor-9-Carboxy-THC in Human Plasma Using Solid Phase Extraction and Gas Chromatography\u2013Mass Spectrometry with Positive Chemical Ionization","volume":"798","author":"Gustafson","year":"2003","journal-title":"J. Chromatogr. B"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1124\/dmd.120.000322","article-title":"Development and Verification of a Linked D9-Thc\/11-Oh-Thc Physiologically Based Pharmacokinetic Model in Healthy, Nonpregnant Population and Extrapolation to Pregnant Womens","volume":"49","author":"Unadkat","year":"2021","journal-title":"Drug Metab. Dispos."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1002\/jps.2600630705","article-title":"Physicochemical Properties, Solubility, and Protein Binding of \u03949-tetrahydrocannabinol","volume":"63","author":"Garrett","year":"1974","journal-title":"J. Pharm. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1023\/B:PHAM.0000029286.45788.ad","article-title":"Creatinine Transport by Basolateral Organic Cation Transporter HOCT2 in the Human Kidney","volume":"21","author":"Urakami","year":"2004","journal-title":"Pharm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3425","DOI":"10.1021\/acs.molpharmaceut.8b00416","article-title":"Importance of OCT2 and MATE1 for the Cimetidine-Metformin Interaction: Insights from Investigations of Polarized Transport in Single- and Double-Transfected MDCK Cells with a Focus on Perpetrator Disposition","volume":"15","author":"Weitz","year":"2018","journal-title":"Mol. Pharm."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/22\/12036\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:29:14Z","timestamp":1760113754000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/22\/12036"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,9]]},"references-count":28,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252212036"],"URL":"https:\/\/doi.org\/10.3390\/ijms252212036","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,9]]}}}