{
    "abstract": "Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals.\nThis study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery.\nThe RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 \u00b1 2.3% and 11 \u00b1 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 \u00b5g h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 \u00b5g h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 \u00b1 0.33 hours at week 3 to 0.77 \u00b1 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 \u00b5g h/L [-0.94, 3.2]) or the diet group (0.94 \u00b5g h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 \u00b1 7%, diet: 3 \u00b1 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 \u00b5g h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/\u00b5g [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals.\nChanges in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.",
    "authors": [
        {
            "affiliation": "Department of Pharmacy, University of Oslo, Blindern, P.O. Box 1068, 0316, Oslo, Norway. k.e.kvitne@farmasi.uio.no.",
            "firstname": "Kine Eide",
            "initials": "KE",
            "lastname": "Kvitne"
        },
        {
            "affiliation": "Department of Pharmacy, University of Oslo, Blindern, P.O. Box 1068, 0316, Oslo, Norway.",
            "firstname": "Markus",
            "initials": "M",
            "lastname": "Hovd"
        },
        {
            "affiliation": "Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, T\u00f8nsberg, Norway.",
            "firstname": "Line Kristin",
            "initials": "LK",
            "lastname": "Johnson"
        },
        {
            "affiliation": "Department of Pharmacy, Uppsala University, Uppsala, Sweden.\nDMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.",
            "firstname": "Christine",
            "initials": "C",
            "lastname": "Wegler"
        },
        {
            "affiliation": "Late-Stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.\nDepartment of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.",
            "firstname": "Cecilia",
            "initials": "C",
            "lastname": "Karlsson"
        },
        {
            "affiliation": "Department of Pharmacy, Uppsala University, Uppsala, Sweden.",
            "firstname": "Per",
            "initials": "P",
            "lastname": "Artursson"
        },
        {
            "affiliation": "Oligonucleotide Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.",
            "firstname": "Shalini",
            "initials": "S",
            "lastname": "Andersson"
        },
        {
            "affiliation": "Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, T\u00f8nsberg, Norway.",
            "firstname": "Rune",
            "initials": "R",
            "lastname": "Sandbu"
        },
        {
            "affiliation": "Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, T\u00f8nsberg, Norway.\nDepartment of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.",
            "firstname": "J\u00f8ran",
            "initials": "J",
            "lastname": "Hjelmes\u00e6th"
        },
        {
            "affiliation": "Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.",
            "firstname": "Eva",
            "initials": "E",
            "lastname": "Skovlund"
        },
        {
            "affiliation": "DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.",
            "firstname": "Rasmus",
            "initials": "R",
            "lastname": "Jansson-L\u00f6fmark"
        },
        {
            "affiliation": "Department of Pharmacy, University of Oslo, Blindern, P.O. Box 1068, 0316, Oslo, Norway.",
            "firstname": "Hege",
            "initials": "H",
            "lastname": "Christensen"
        },
        {
            "affiliation": "Department of Pharmacy, University of Oslo, Blindern, P.O. Box 1068, 0316, Oslo, Norway.\nDepartment of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.",
            "firstname": "Anders",
            "initials": "A",
            "lastname": "\u00c5sberg"
        },
        {
            "affiliation": "Department of Pharmacy, University of Oslo, Blindern, P.O. Box 1068, 0316, Oslo, Norway.",
            "firstname": "Ida",
            "initials": "I",
            "lastname": "Robertsen"
        }
    ],
    "conclusions": null,
    "copyrights": "\u00a9 2023. The Author(s).",
    "doi": "10.1007/s40262-023-01320-9\n10.1001/jamanetworkopen.2022.35003\n10.1001/jamasurg.2013.3654\n10.1016/s0140-6736(21)00591-2\n10.1111/obr.12869\n10.1111/bcp.14913\n10.1111/bcp.15349\n10.1111/cts.13142\n10.1007/s11095-015-1752-9\n10.1111/bcpt.13234\n10.1002/phar.1560\n10.1007/s11695-017-2745-z\n10.1007/s40262-023-01235-5\n10.1007/978-1-60761-416-6_10\n10.1016/j.pharmthera.2005.06.005\n10.1021/acs.molpharmaceut.0c00574\n10.1023/a:1026183200740\n10.1002/jcph.200\n10.2165/00003088-197702010-00001\n10.1007/s13318-022-00802-8\n10.1136/bmjopen-2018-021878\n10.1002/cpt.2558\n10.1016/j.jprot.2014.07.012\n10.1097/FTD.0b013e31825c4ba6\n10.7326/0003-4819-150-9-200905050-00006\n10.1053/j.gastro.2009.06.005\n10.1124/dmd.111.041012\n10.1111/fcp.12687\n10.1111/bph.15298\n10.1016/0002-8703(81)90100-9\n10.1172/jci6663\n10.1161/01.cir.44.5.810\n10.1007/s11897-011-0076-2\n10.1097/crd.0000000000000028\n10.1038/s41598-020-69326-y\n10.1186/s12882-017-0474-0",
    "journal": "Clinical pharmacokinetics",
    "keywords": [],
    "methods": null,
    "publication_date": "2023-11-23",
    "pubmed_id": "37993699\n36205997\n24352617\n33965067\n31232513\n33990981\n35404513\n34435745\n26202517\n30916845\n25757445\n28560524\n36988826\n19949926\n16209890\n33886332\n14620513\n24166743\n581950\n322907\n36319903\n29844102\n35158408\n25063446\n22722776\n19414839\n19524579\n21878559\n33914974\n33119943\n7282520\n10411543\n5115072\n22135185\n25093738\n32719417\n28166744",
    "results": "The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 \u00b1 2.3% and 11 \u00b1 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 \u00b5g h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 \u00b5g h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 \u00b1 0.33 hours at week 3 to 0.77 \u00b1 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 \u00b5g h/L [-0.94, 3.2]) or the diet group (0.94 \u00b5g h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 \u00b1 7%, diet: 3 \u00b1 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 \u00b5g h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/\u00b5g [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals.",
    "title": "Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals.",
    "xml": "<Element 'PubmedArticle' at 0x78850322f740>"
}