نتائج البحث - "Hjelmesæth, J"

الوصف: Background and Objective 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. Methods This 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. Results The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 +/- 2.3% and 11 +/- 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 mu g h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 mu g 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 +/- 0.33 hours at week 3 to 0.77 +/- 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 mu g h/L [-0.94, 3.2]) or the diet group (0.94 mu g h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 +/- 7%, diet: 3 +/- 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 mu g 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/mu g [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals. Conclusions Changes 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.

الوصول الحر: https://gup.ub.gu.se/publication/332010Test

6

دورية أكاديمية

A Comparative Analysis of Cytochrome P450 Activities in Paired Liver and Small Intestinal Samples from Patients with Obesity

المؤلفون: Krogstad, V, Peric, A, Robertsen, I, Kringen, MK, Wegler, C, Angeles, PC, Hjelmesaeth, J, Karlsson, C, Andersson, S, Artursson, P, Asberg, A, Andersson, TB, Christensen, H

المصدر: Drug metabolism and disposition: the biological fate of chemicals. 48(1):8-17

مصطلحات موضوعية: Medicin och hälsovetenskap

الوصول الحر: http://kipublications.ki.se/Default.aspx?queryparsed=id:142801743Test

النص الكامل

7

Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance

المؤلفون: Hovd, M., Robertsen, I., Johnson, L. K., Krogstad, V., Wegler, C., Kvitne, K. E., Kringen, M. K., Skovlund, E., Karlsson, Cecilia, Andersson, S., Artursson, P., Sandbu, R., Hjelmesaeth, J., Asberg, A., Jansson-Lofmark, R., Christensen, H.

المصدر: Clinical Pharmacokinetics. 62(5):725-735

مصطلحات موضوعية: Pharmacology and Toxicology, Farmakologi och toxikologi, liver, digestion, efficacy, 1b1, Pharmacology & Pharmacy

الوصف: IntroductionRosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity.MethodsPatients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day).ResultsA total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant.ConclusionsNeither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.

الوصول الحر: https://gup.ub.gu.se/publication/326536Test

8

دورية أكاديمية

Drug Disposition Protein Quantification in Matched Human Jejunum and Liver From Donors With Obesity

المؤلفون: Wegler, C., Wisniewski, J., Robertsen, I., Christensen, H., Hertel, J., Hjelmesaeth, J., Jansson-Lofmark, R., Asberg, A., Andersson, T., Artursson, P.

المصدر: Clinical Pharmacology & Therapeutics

الوصف: Mathematical models, such as physiologically-based pharmacokinetic models, are used to predict, for example, drug disposition and toxicity. However, populations differ in the abundance of proteins involved in these processes. To improve the building and refinement of such models, they must take into account these interindividual variabilities. In this study, we used global proteomics to characterize the protein composition of jejunum and liver from 37 donors with obesity enrolled in the COCKTAIL study. Liver protein levels from the 37 donors were further compared with those from donors without obesity. We quantified thousands of proteins and could present the expression of several drug-metabolizing enzymes, for the first time, in jejunum, many of which belong to the cytochrome P450 (CYP) (e.g., CYP2U1) and the amine oxidase (flavin-containing) (e.g., monoamine oxidase A (MAOA)) families. Although we show that many metabolizing enzymes had greater expression in liver, others had higher expression in jejunum (such as, MAOA and CES2), indicating the role of the small intestine in extrahepatic drug metabolism. We further show that proteins involved in drug disposition are not correlated in the two donor-matched tissues. These proteins also do not correlate with physiological factors such as body mass index, age, and inflammation status in either tissue. Furthermore, the majority of these proteins are not differently expressed in donors with or without obesity. Nonetheless, interindividual differences were considerable, with implications for personalized prediction models and systems pharmacology.

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/21.11116/0000-000A-1FD6-3Test; http://hdl.handle.net/21.11116/0000-000A-1FD8-1Test

الإتاحة: https://doi.org/10.1002/cpt.2558Test
http://hdl.handle.net/21.11116/0000-000A-1FD6-3Test
http://hdl.handle.net/21.11116/0000-000A-1FD8-1Test

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9

دورية أكاديمية

Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL)

المؤلفون: Hjelmesaeth, J, Asberg, A, Andersson, S, Sandbu, R, Robertsen, I, Johnson, LK, Angeles, PC, Hertel, JK, Skovlund, E, Heijer, M, Ek, AL, Krogstad, V, Karlsen, TI, Christensen, H, Andersson, TB, Karlsson, C

المصدر: BMJ open. 8(5):e021878

مصطلحات موضوعية: Medicin och hälsovetenskap

الوصول الحر: http://kipublications.ki.se/Default.aspx?queryparsed=id:138549290Test

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النص الكامل

10

دورية أكاديمية

Proteomics-informed prediction of rosuvastatin plasma profiles in patients with a wide range of body weight.

المؤلفون: Wegler, C., Prieto Garcia, L., Klinting, S., Robertsen, I., Wiśniewski, J., Hjelmesaeth, J., Asberg, A., Jansson-Lofmark, R., Andersson, T., Artursson, P.

المصدر: Clinical pharmacology and therapeutics

الوصف: Rosuvastatin is a frequently used probe to study transporter-mediated hepatic uptake. Pharmacokinetic models have therefore been developed to predict transporter impact on rosuvastatin disposition in vivo. However, the inter-individual differences in transporter concentrations were not considered in these models, and the predicted transporter impact was compared with historical in vivo data. In this study, we investigated the influence of inter-individual transporter concentrations on the hepatic uptake clearance of rosuvastatin in 54 patients covering a wide range of body weight. The 54 patients were given an oral dose of rosuvastatin the day before undergoing gastric bypass or cholecystectomy, and pharmacokinetic parameters were established from each patient's individual time-concentration profiles. Liver biopsies were sampled from each patient and their individual hepatic transporter concentrations were quantified. We combined the transporter concentrations with in vitro uptake kinetics determined in HEK293-transfected cells, and developed a semi-mechanistic model with a bottom-up approach to predict the plasma concentration profiles of the single dose of rosuvastatin in each patient. The predicted pharmacokinetic parameters were evaluated against the measured in vivo plasma pharmacokinetics from the same 54 patients. The developed model predicted the rosuvastatin pharmacokinetics within two-fold error for rosuvastatin AUC (78% of the patients; AFE: 0.96), Cmax (76%; AFE: 1.05), and t1/2 (98%; AFE: 0.89), and captured differences in the rosuvastatin pharmacokinetics in patients with the OATP1B1 521T

وصف الملف: application/pdf; application/vnd.openxmlformats-officedocument.spreadsheetml.sheet

العلاقة: http://hdl.handle.net/21.11116/0000-0007-DF8E-FTest; http://hdl.handle.net/21.11116/0000-0007-DF90-BTest; http://hdl.handle.net/21.11116/0000-0007-DF91-ATest; http://hdl.handle.net/21.11116/0000-0007-DF92-9Test

الإتاحة: https://doi.org/10.1002/cpt.2056Test
http://hdl.handle.net/21.11116/0000-0007-DF8E-FTest
http://hdl.handle.net/21.11116/0000-0007-DF90-BTest
http://hdl.handle.net/21.11116/0000-0007-DF91-ATest
http://hdl.handle.net/21.11116/0000-0007-DF92-9Test

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