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| 3. |
- Kvitne, K. E., et al.
(författare)
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Correlations between 4 beta-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range
- 2022
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 78:8, s. 1289-1299
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4 beta-hydroxycholesterol (4 beta OHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4 beta OHC 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 4 beta OHC 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 4 beta OHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (rho = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (rho = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (rho = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (rho = 0.15, p = 0.53). 4 beta OHC concentrations correlated weakly with midazolam absolute bioavailability (rho = - 0.23, p = 0.027) and apparent oral clearance (rho = 0.28, p = 0.008), but not with systemic clearance (rho = - 0.03, p = 0.81). Conclusion These findings suggest that 4 beta OHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4 beta OHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.
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- Andersson-Engels, S., et al.
(författare)
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Tissue diagnostics using laser-induced fluorescence
- 1989
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Ingår i: Berichte der Bunsengesellschaft für Physikalische Chemie. - : Wiley. - 0005-9021. ; 93:3, s. 335-342
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Tidskriftsartikel (refereegranskat)abstract
- We have performed extensive investigations of laser-induced fluorescence in animal and human tissue aimed at instant tissue characterization. Autofluorescence, as well as specific fluorescence from HPD/DHE and other photosensitizers, has been utilized. The studies have been focused on the demarcation of malignant tumours and atheroscleortic plaques. A nitrogen laser or an excimer-pumped dye laser was used to induce fluorescence, which was analysed with an intensified optical multichannel system. A fibre-optic sensor system was developed for the clinical work. Multi-colour fluorescence imaging has also been demonstrated along a line and equipment for two-dimensional imaging is being constructed. Dimensionless spectroscopic functions, which are not affected by factors that are clinically uncontrollable have been employed for optimum tissue discrimination. The investigations have so far been performed in a time-integrated mode, but time-resolved studies are now being initiated to fully exploit the diagnostic power of tissue laser-induced fluorescence. In addition to a presentation of our own work a brief review of tissue fluorescence studies performed by other groups is also given.
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| 5. |
- Charette, M. A., et al.
(författare)
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The Transpolar Drift as a Source of Riverine and Shelf-Derived Trace Elements to the Central Arctic Ocean
- 2020
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Ingår i: Journal of Geophysical Research-Oceans. - : American Geophysical Union (AGU). - 2169-9275 .- 2169-9291. ; 125:5
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Tidskriftsartikel (refereegranskat)abstract
- A major surface circulation feature of the Arctic Ocean is the Transpolar Drift (TPD), a current that transports river-influenced shelf water from the Laptev and East Siberian Seas toward the center of the basin and Fram Strait. In 2015, the international GEOTRACES program included a high-resolution pan-Arctic survey of carbon, nutrients, and a suite of trace elements and isotopes (TEIs). The cruises bisected the TPD at two locations in the central basin, which were defined by maxima in meteoric water and dissolved organic carbon concentrations that spanned 600 km horizontally and similar to 25-50 m vertically. Dissolved TEIs such as Fe, Co, Ni, Cu, Hg, Nd, and Th, which are generally particle-reactive but can be complexed by organic matter, were observed at concentrations much higher than expected for the open ocean setting. Other trace element concentrations such as Al, V, Ga, and Pb were lower than expected due to scavenging over the productive East Siberian and Laptev shelf seas. Using a combination of radionuclide tracers and ice drift modeling, the transport rate for the core of the TPD was estimated at 0.9 +/- 0.4 Sv (10(6) m(3)s(-1)). This rate was used to derive the mass flux for TEIs that were enriched in the TPD, revealing the importance of lateral transport in supplying materials beneath the ice to the central Arctic Ocean and potentially to the North Atlantic Ocean via Fram Strait. Continued intensification of the Arctic hydrologic cycle and permafrost degradation will likely lead to an increase in the flux of TEIs into the Arctic Ocean. Plain Language Summary A major feature of the Arctic Ocean circulation is the Transpolar Drift (TPD), a surface current that carries ice and continental shelf-derived materials from Siberia across the North Pole to the North Atlantic Ocean. In 2015, an international team of oceanographers conducted a survey of trace elements in the Arctic Ocean, traversing the TPD. Near the North Pole, they observed much higher concentrations of trace elements in surface waters than in regions on either side of the current. These trace elements originated from land, and their journey across the Arctic Ocean is made possible by chemical reactions with dissolved organic matter that originates mainly in Arctic rivers. This study reveals the importance of rivers and shelf processes combined with strong ocean currents in supplying trace elements to the central Arctic Ocean and onward to the Atlantic. These trace element inputs are expected to increase as a result of permafrost thawing and increased river runoff in the Arctic, which is warming at a rate much faster than anywhere else on Earth. Since many of the trace elements are essential building blocks for ocean life, these processes could lead to significant changes in the marine ecosystems and fisheries of the Arctic Ocean.
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| 6. |
- Charette, M, et al.
(författare)
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The Transpolar Drift as a Source of Riverine and Shelf‐Derived Trace Elements to the Central Arctic Ocean
- 2020
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Ingår i: Journal of Geophysical Research - Oceans. - 2169-9275 .- 2169-9291. ; 125, s. 1-34
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Tidskriftsartikel (refereegranskat)abstract
- A major surface circulation feature of the Arctic Ocean is the Transpolar Drift (TPD), a current that transports river‐influenced shelf water from the Laptev and East Siberian Seas toward the center of the basin and Fram Strait. In 2015, the international GEOTRACES program included a high‐resolution pan‐Arctic survey of carbon, nutrients, and a suite of trace elements and isotopes (TEIs). The cruises bisected the TPD at two locations in the central basin, which were defined by maxima in meteoric water and dissolved organic carbon concentrations that spanned 600 km horizontally and ~25–50 m vertically. Dissolved TEIs such as Fe, Co, Ni, Cu, Hg, Nd, and Th, which are generally particle‐reactive but can be complexed by organic matter, were observed at concentrations much higher than expected for the openocean setting. Other trace element concentrations such as Al, V, Ga, and Pb were lower than expected due to scavenging over the productive East Siberian and Laptev shelf seas. Using a combination of radionuclide tracers and ice drift modeling, the transport rate for the core of the TPD was estimated at 0.9 ± 0.4 Sv(106m3 s−1). This rate was used to derive the mass flux for TEIs that were enriched in the TPD, revealing the importance of lateral transport in supplying materials beneath the ice to the central Arctic Ocean and potentially to the North Atlantic Ocean via Fram Strait. Continued intensification of the Arctic hydrologicc ycle and permafrost degradation will likely lead to an increase in the flux of TEIs into the Arctic Ocean.
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| 7. |
- Kvitne, K. E., et al.
(författare)
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Short- and long-term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity
- 2022
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 88:9, s. 4121-4133
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Tidskriftsartikel (refereegranskat)abstract
- Aim 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.
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| 8. |
- Kvitne, K. E., et al.
(författare)
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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
- 2022
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Ingår i: Cts-Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 15:1, s. 221-233
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Tidskriftsartikel (refereegranskat)abstract
- It remains uncertain whether pharmacokinetic changes following Roux-en-Y gastric bypass (RYGB) can be attributed to surgery-induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short- and long-term effects of RYGB and calorie restriction on CYP3A-activity, and cross-sectionally compare CYP3A-activity with normal weight to overweight controls using midazolam as probe drug. This three-armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) 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) followed by a 6-week very-low-energy-diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight-loss at week 9 (13 +/- 2.4% vs. 11 +/- 3.6%), but differed substantially after 2 years (-30 +/- 7.0% vs. -3.1 +/- 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 +/- 7.5% in the RYGB group and 32 +/- 6.1% in the diet group at year 2 compared with baseline, with no between-group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A-activity is not only dependent on weight-loss through RYGB.
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