Kine Eide Kvitne

• Kvitne, Kine Eide; Hovd, Markus; Johnsen, Line Kristin; Wegler, Christine; Karlsson, Cecilia & Artursson, Per [Show all 14 contributors for this article] (2023). Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals. Clinical Pharmacokinetics. ISSN 0312-5963. doi: 10.1007/s40262-023-01320-9. Full text in Research Archive
• Kvitne, Kine Eide; Drevland, Ole Martin; Haugli, Nora; Skadberg, Eline Supannee Setu; Zare, Hasse Khiabani & Åsberg, Anders [Show all 7 contributors for this article] (2023). Intraindividual Variability in Absolute Bioavailability and Clearance of Midazolam in Healthy Individuals. Clinical Pharmacokinetics. ISSN 0312-5963. 62(7), p. 981–987. doi: 10.1007/s40262-023-01257-z. Full text in Research Archive
• Hovd, Markus Herberg; Robertsen, Ida; Johnson, Line Kristin; Krogstad, Veronica; Wegler, Christine & Kvitne, Kine Eide [Show all 16 contributors for this article] (2023). Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance. Clinical Pharmacokinetics. ISSN 0312-5963. 62(5), p. 725–735. doi: 10.1007/s40262-023-01235-5. Full text in Research Archive
• Kvitne, Kine Eide; Åsberg, Anders; Johnson, Line Kristin; Wegler, Christine; Hertel, Jens Kristoffer & Artursson, Per [Show all 14 contributors for this article] (2022). Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity. Clinical and Translational Science (CTS). ISSN 1752-8054. 15(11), p. 2685–2696. doi: 10.1111/cts.13394. Full text in Research Archive Show summary

  Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross-sectional analysis; 29 with T2DM and obesity (T2DM-obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (−0.39 [95% CI: −0.82, −0.09]) and 40% (−0.09 fmol/μg protein [95% CI: −0.18, −0.003]) lower in T2DM-obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform-specific.

• Kvitne, Kine Eide; Hole, Kristine; Krogstad, Veronica; Wollmann, Birgit Malene Tovik; Wegler, Christine & Johnson, Line Kristin [Show all 19 contributors for this article] (2022). Correlations between 4β-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range. European Journal of Clinical Pharmacology. ISSN 0031-6970. 78(8), p. 1289–1299. doi: 10.1007/s00228-022-03336-9. Full text in Research Archive Show summary

  Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4β-hydroxycholesterol (4βOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4βOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4βOHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4βOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (ρ = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (ρ = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (ρ = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (ρ = 0.15, p = 0.53). 4βOHC concentrations correlated weakly with midazolam absolute bioavailability (ρ =  − 0.23, p = 0.027) and apparent oral clearance (ρ = 0.28, p = 0.008), but not with systemic clearance (ρ =  − 0.03, p = 0.81). Conclusion These findings suggest that 4βOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4βOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.

• Kvitne, Kine Eide; Krogstad, Veronica; Wegler, Christine; Johnson, Line Kristin; Kringen, Marianne K. & Hovd, Markus Herberg [Show all 19 contributors for this article] (2022). Short- and long-term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity. British Journal of Clinical Pharmacology. ISSN 0306-5251. 88(9), p. 4121–4133. doi: 10.1111/bcp.15349. Full text in Research Archive Show summary

  Roux-en-Y gastric bypass (RYGB) may influence drug disposition due to surgery-induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short- and long-term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5-hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross-sectionally compare these CYP-activities with normal-to-overweight controls. Methods This trial included patients with severe obesity preparing for RYGB (n = 40) or diet-induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day, weeks 0-3) followed by a 6-week very-low-energy diet or RYGB (both <800 kcal/day, weeks 3-9). Follow-up time was 2 years, with four pharmacokinetic investigations. Results Mean ± SD weight loss from baseline was similar in the RYGB-group (13 ± 2.4%) and the diet group (10.5 ± 3.9%) at week 9, but differed at year 2 (RYGB −30 ± 6.9%, diet −3.1 ± 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3-9), but not in the diet-group (between-group difference −0.30 [−0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7-fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. Conclusion Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed.

• Kvitne, Kine Eide; Robertsen, Ida; Skovlund, Eva; Christensen, Hege Staaland; Krogstad, Veronica & Wegler, Christine [Show all 18 contributors for this article] (2021). Short- and long-term effects of body weight loss following calorie restriction and gastric bypass on CYP3A-activity – a non-randomized three-armed controlled trial. Clinical and Translational Science (CTS). ISSN 1752-8054. doi: 10.1111/cts.13142. Full text in Research Archive
• Strøm Halden, Thea Anine; Kvitne, Kine Eide; Midtvedt, Karsten; Rajakumar, Laavanyaah; Robertsen, Ida & Brox, Jan [Show all 10 contributors for this article] (2019). Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus. Diabetes Care. ISSN 0149-5992. 42(6), p. 1067–1074. doi: 10.2337/dc19-0093. Full text in Research Archive

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• Kvitne, Kine Eide; Hole, Kristine; Molden, Espen & Robertsen, Ida (2022). Response to: “Utility of endogenous 4β-hydroxycholesterol as a biomarker to assess cytochrome P 450 3A (CYP3A) activity: not quite ready for prime time”. European Journal of Clinical Pharmacology. ISSN 0031-6970. doi: 10.1007/s00228-022-03387-y.

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