{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:17:38Z","timestamp":1791893858134,"version":"4.3.4"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:p>\n                    OATP1B, P\u2010gp, BCRP, and CYP3A are the most contributing drug\u2010metabolizing enzymes or transporters (DMETs) for commonly prescribed medication. Their activities may change in end\u2010stage renal disease (ESRD) patients with large inter\u2010individual variabilities (IIVs), leading to altered substrate drug exposure and ultimately elevated safety risk. However, the changing extent and indictive influencing factors are not quantified so far. Here, a microdose cocktail regimen containing five sensitive substrate drugs (pitavastatin, dabigatran etexilate, rosuvastatin, midazolam, and atorvastatin) for these DMETs was administrated to Chinese healthy volunteers and ESRD patients. Drug pharmacokinetics profiles were determined, together with physiological, pharmacogenetic, and gut microbiome signature. Population pharmacokinetic and machine learning model were established to identify key influencing factors and quantify their contribution to drug exposure change. The exposure of pitavastatin, dabigatran, rosuvastatin, and atorvastatin increased to 1.8\u2010, 3.1\u2010, 1.1\u2010, and 1.3\u2010fold, respectively, whereas midazolam exposure decreased by 72% in ESRD patients. Notably, in addition to disease state, the relative abundance of genus\n                    <jats:italic>Veillonella<\/jats:italic>\n                    and\n                    <jats:italic>Clostridium_XIVb<\/jats:italic>\n                    were firstly identified as significant influencing factors for PTV and RSV apparent clearance, respectively, suggesting their indicative role for OATP and BCRP activity evaluation. Moreover, several genera were found to strongly associate with drug clearance and reduce unexplained IIVs. Accordingly, it was estimated that OATP1B and intestine P\u2010gp activity decreased by 35\u201375% and 29\u201344%, respectively, whereas BCRP and CYP3A4 activity may upregulate to some extent. Our study provides a quantitative and mechanistic understanding of individual DMET activity and could support precision medicine of substrate drugs in ESRD patients.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3546","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T03:35:19Z","timestamp":1736480119000},"page":"1303-1312","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Microdose Cocktail Study Reveals the Activity and Key Influencing Factors of\n                    <scp>OATP1B<\/scp>\n                    , P\u2010Gp,\n                    <scp>BCRP,<\/scp>\n                    and\n                    <scp>CYP3A<\/scp>\n                    in End\u2010Stage Renal Disease Patients"],"prefix":"10.1002","volume":"117","author":[{"given":"Weijie","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"},{"name":"Drug Clinical Trial Center Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuejuan","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"},{"name":"Drug Clinical Trial Center Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyi","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"},{"name":"Drug Clinical Trial Center Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenbin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinkui","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhong","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Feng","sequence":"additional","affiliation":[{"name":"Drug Clinical Trial Center Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyan","family":"Jin","sequence":"additional","affiliation":[{"name":"Drug Clinical Trial Center Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"},{"name":"Drug Clinical Trial Center Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Li","sequence":"additional","affiliation":[{"name":"Drug Clinical Trial Center Peking University Third Hospital  Beijing China"},{"name":"Institute of Medical Innovation Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4382-3704","authenticated-orcid":false,"given":"Hao","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"},{"name":"Drug Clinical Trial Center Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2263-2979","authenticated-orcid":false,"given":"Wen","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Nephrology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0608-8192","authenticated-orcid":false,"given":"Dongyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Drug Clinical Trial Center Peking University Third Hospital  Beijing China"},{"name":"Institute of Medical Innovation Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60687-X"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2022.6817"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.399"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.01030120"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000520028"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15563"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1851"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00750-8"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.525"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1998"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.726669"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.337"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.807"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1159\/000514550"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270011413588"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-022-01184-5"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-35808-6"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S362607"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1098"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1875"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins13040246"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adg8357"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2647"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12785"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-023-01578-y"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/jf4007505"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-023-03056-y"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-021-01032-y"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-150-9-200905050-00006"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1205"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00430.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-018-3583-y"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3077"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157-013-0806-8"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60674-5"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2020.10.004"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.35371"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60716-8"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.09.051"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010050459"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfs416"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.014113"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)91209-6"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2023.06.021"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2021040538"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-198311000-00005"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3546","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T11:16:03Z","timestamp":1764760563000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3546"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,10]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1002\/cpt.3546"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3546","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,10]]},"assertion":[{"value":"2024-09-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}