{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T16:23:43Z","timestamp":1785515023055,"version":"3.56.0"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>\n                    The widely prescribed oral anti\u2010diabetic drug metformin is eliminated unchanged in the urine primarily through active tubular secretion. This process is mediated by organic cation transporter 2 (OCT2), an uptake transporter expressed on the basolateral membrane of renal proximal tubule cells. Metformin uptake into the liver, the site of action, is mediated by organic cation transporter 1 (OCT1), which is expressed on the sinusoidal membrane of hepatocytes. Sixteen healthy adults participated in a clinical pharmacokinetic drug\u2013drug interaction study in which they were orally administered metformin (50\u2009mg) as a dual OCT1\/2 substrate alone (baseline) and with cimetidine (400\u2009mg) as an OCT inhibitor. Relative to baseline, metformin systemic plasma exposure increased by 24% (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) in the presence of cimetidine, which was accompanied by a disproportional decrease (8%) in metformin renal clearance (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.005). Genetic variants of\n                    <jats:italic>OCT1<\/jats:italic>\n                    and\n                    <jats:italic>OCT2<\/jats:italic>\n                    moderately impacted the significance and magnitude of the interaction. Collectively, we hypothesized that the cimetidine\u2013metformin interaction involves inhibition of hepatic OCT1 as well as renal OCT2. We tested this hypothesis by developing a physiologically based pharmacokinetic (PBPK) model and assessing potential OCT biomarkers in plasma and urine to gain mechanistic insight into the transporters involved in this interaction. The PBPK model predicted that cimetidine primarily inhibits hepatic OCT1 and, to a lesser extent, renal OCT2. The unchanged renal clearance of potential OCT2 biomarkers following cimetidine exposure supports a minimal role for renal OCT2 in this interaction.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3639","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T01:39:35Z","timestamp":1742261975000},"page":"343-354","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Quantitative Contributions of Hepatic and Renal Organic Cation Transporters to the Clinical Pharmacokinetic Cimetidine\u2013Metformin Interaction"],"prefix":"10.1002","volume":"118","author":[{"given":"Anoud Sameer","family":"Ailabouni","sequence":"first","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences Washington State University  Spokane Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilip Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences Washington State University  Spokane Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3906-5250","authenticated-orcid":false,"given":"Aarzoo","family":"Thakur","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences Washington State University  Spokane Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3044-5521","authenticated-orcid":false,"given":"Erin C.","family":"Boone","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology &amp; Therapeutic Innovation Children's Mercy Research Institute  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-1893","authenticated-orcid":false,"given":"Andrea","family":"Gaedigk","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology &amp; Therapeutic Innovation Children's Mercy Research Institute  Kansas City Missouri USA"},{"name":"School of Medicine, Department of Pediatrics University of Missouri\u2010Kansas City  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3331-1839","authenticated-orcid":false,"given":"Mary F.","family":"Paine","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences Washington State University  Spokane Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9090-0912","authenticated-orcid":false,"given":"Bhagwat","family":"Prasad","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences Washington State University  Spokane Washington USA"},{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2017.04.078"},{"key":"e_1_2_10_2_1","first-page":"2532","article-title":"Is metformin a perfect drug? Updates in pharmacokinetics and pharmacodynamics","volume":"23","author":"Magdalena M.\u2010P.","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.2165\/11534750-000000000-00000"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30558"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1002\/cpt.2666","article-title":"Challenges and opportunities for improved drug\u2013drug interaction predictions for renal OCT2 and MATE1\/2\u2010K transporters","volume":"112","author":"Krishnan S.","year":"2022","journal-title":"Clin. Pharmacol. 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