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Dive into the research topics where Jan Leo Egge Reubsaet is active.

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Featured researches published by Jan Leo Egge Reubsaet.


Transplantation | 2008

Declining intracellular T-lymphocyte concentration of cyclosporine a precedes acute rejection in kidney transplant recipients.

Pål Falck; Anders Åsberg; Heidi Guldseth; Sara Bremer; Fatemeh Akhlaghi; Jan Leo Egge Reubsaet; Per Pfeffer; Anders Hartmann; Karsten Midtvedt

Background. We investigated cyclosporine A (CsA) concentrations at the site of action, inside T-lymphocytes, to evaluate its applicability as a new supplementary therapeutic drug monitoring method after renal transplantation. Method. In this prospective single-center study, 20 kidney transplant recipients, mean age 54 (range 21–74) years, on CsA-based immunosuppression were included within 2 weeks posttransplant and followed for 3 months. Nine patients also had one full 12-hour pharmacokinetic profile performed. T-lymphocytes were isolated from 7 ml whole blood using Prepacyte and intracellular CsA concentrations were determined using a validated liquid chromatography double mass spectrometry method. Results. Seven patients (35%) experienced acute rejections (all biopsy verified) during the first three months posttransplantation. Intracellular CsA concentrations tended to decline 1 week prior to acute rejection and the decrease was significant (−27.1±14.6%, P=0.014) three days before the rejection episodes were recognized clinically. In addition, the intracellular CsA area under the curve 0–12 measured during stable phase was 182% higher in the rejection-free patients (P=0.004). There was no difference between patients experiencing rejection and the rejection-free patients with respect to CsA C2-levels, dose (mg/kg), human leukocyte antigen mismatch, donor age, recipient age, or ABCB1 genotyping. Conclusion. Intracellular CsA T-lymphocyte concentrations declined significantly 3 days prior to a rejection episode and there was a general lower intracellular exposure of CsA in recipients experiencing rejection. Intracellular measurement of CsA therefore seems to have a potential to further improve individualization of therapeutic drug monitoring. Larger studies are needed to elucidate the role for intracellular T-lymphocyte measurements in ordinary clinical care, for both CsA and other immunosuppressive drugs.


Clinical Pharmacology & Therapeutics | 2009

Significantly altered systemic exposure to atorvastatin acid following gastric bypass surgery in morbidly obese patients.

I B Skottheim; Kjell Morten Stormark; Hege Christensen; Gunn Signe Jakobsen; Jøran Hjelmesæth; Trond Jenssen; Jan Leo Egge Reubsaet; Rune Sandbu; Anders Åsberg

The impact of gastric bypass on atorvastatin pharmacokinetics was investigated in 12 morbidly obese patients being treated with 20–80 mg atorvastatin each morning. Eight‐hour pharmacokinetic investigations were performed the day before the surgery and at a median of 5 weeks (range 3–6 weeks) after the surgery. Gastric bypass surgery produced a variable effect on individual systemic exposure to atorvastatin acid (area under the plasma concentration vs. time curve from 0 to 8 h postdose (AUC(0–8))), ranging from a threefold decrease to a twofold increase (median ratio = 1.1, P = 0.99). Patients with the highest systemic exposure to atorvastatin before surgery showed reduced exposure after surgery (n = 3, median ratio = 0.4, range = 0.3–0.5, P < 0.01), whereas those with lower systemic exposure before surgery showed a median 1.2‐fold increase in atorvastatin AUC(0–8) (n = 9, range = 0.8–2.3, P = 0.03) after surgery. This study indicates that the presurgical first‐pass metabolic capacity influences the effect of gastric bypass on atorvastatin bioavailability. Because individual first‐pass metabolic capacity is not readily assessable clinically, retitration up to the lowest effective dose should be performed after the surgery.


Clinical Pharmacology & Therapeutics | 2004

Substantially elevated levels of atorvastatin and metabolites in cyclosporine-treated renal transplant recipients

Monica Hermann; Anders Åsberg; Hege Christensen; Hallvard Holdaas; Anders Hartmann; Jan Leo Egge Reubsaet

o the Editor: In the work of Hedman et al recently presented in the ournal, a 10-fold higher systemic exposure of pravastatin comined with unaffected terminal half-life was observed in pediatic patients undergoing immunosuppressive therapy compared ith hypercholesterolemic children. We here report similar reults for atorvastatin and cyclosporine (INN, cicloporin). Previously, we performed a study to investigate the pharmaokinetic interaction between atorvastatin and cyclosporine in enal transplant recipients, where analysis of atorvastatin was erformed by an enzyme inhibition assay. We have now perormed additional analyses by specific HPLC with tandem mass pectrometric detection and included a control group to enable urther investigation of the effect of cyclosporine on the pharacokinetics of atorvastatin and metabolites. In brief, 18 renal transplant recipients undergoing yclosporine-based immunosuppressive therapy were adminisered 10 mg atorvastatin daily for 4 weeks. At the end of 4 eeks of treatment, plasma samples for pharmacokinetic analyis were drawn at fixed time intervals from 0 hours (before dose dministration) to 24 hours after dosing. Eighteen age-matched, ealthy individuals (median age, 47 years [range, 30-60 years]; edian serum creatinine level, 93 mol/L [range, 70-115 mol/ ]) were included in the study to serve as a control group and ere administered 10 mg atorvastatin daily for 1 week. All articipants gave written informed consent. The mean plasma level versus time curves for both acid and actone forms of atorvastatin, oand p-hydroxyatorvastatin, are hown in Fig 1. Systemic exposure of atorvastatin and its meabolites was substantially higher in the patient group compared ith the control group, and the differences were about 2-fold reater for acid forms than for lactones (Table I). No statistically ignificant difference was observed for the terminal half-life etween the 2 groups (Table I). The mechanism of the interaction between atorvastatin and yclosporine is probably complex, as both drugs are metablized by cytochrome P450 (CYP) 3A4 and as cyclosporine as the potential to inhibit several drug transporters expected o be involved in the disposition of atorvastatin. The subtantial increase in systemic exposure combined with unalered terminal half-life could indicate an increased bioavailbility of atorvastatin by inhibition of intestinal efflux


Transplantation | 2008

Reduced elimination of cyclosporine A in elderly (>65 years) kidney transplant recipients.

Pål Falck; Anders Åsberg; Karen-Therese Byberg; Sara Bremer; Stein Bergan; Jan Leo Egge Reubsaet; Karsten Midtvedt

Background. Physiologic functions that may affect pharmacokinetics of drugs are altered in elderly patients. The current study was performed to elucidate the effect of age on cyclosporine A (CsA) pharmacokinetics in renal transplant recipients. Method. Twenty-five renal transplant recipients on CsA treatment were included in the study. CsA doses were adjusted by C2 monitoring. The patients were divided into two groups based on age; elderly: more than 65 years (n=11, mean 73 years) and younger: 18 to 64 years (n=14, mean 43 years). A full 12-hr pharmacokinetic profile was performed during stable phase. CsA whole blood and intracellular T-lymphocytes concentrations (first 6 hr) were measured. Genotyping of the CYP3A5*1/*3 and ABCB1 (C1236T, G2677T, C3435T) polymorphisms and quantification of whole blood mRNA ABCB1 expression were performed in all patients. Results. Elderly patients achieved target C2 levels with lower CsA doses than the younger patients (4.3±0.8 vs. 6.1±2.1 mg/day/kg, P=0.025) because of lower clearance of CsA (22.7±5.1 vs. 30.5±11.1 L/hr, P=0.031). Elderly patients also showed 44% higher intracellular-to-whole blood CsA ratio than younger patients (P=0.02). Neither the CYP3A5*1, the ABCB1 genotypes nor mRNA ABCB1 expression revealed any significant influence on CsA pharmacokinetics. Conclusion. The clearance of CsA decreased with increasing age. In addition, elderly patients had a significant larger proportion of the whole blood CsA concentration located at the site of action (within T lymphocytes). This indicates that in elderly recipients it might be safe to aim for an even lower whole blood target levels than current guidelines propose.


Journal of Pharmaceutical and Biomedical Analysis | 2004

Sample preparation and determination of gabapentin in venous and capillary blood using liquid chromatography-tandem mass spectrometry

K.C. Carlsson; Jan Leo Egge Reubsaet

An analytical method for the determination of gabapentin in serum obtained from venous blood samples has been developed using high-performance liquid chromatography (HPLC)-tandem mass spectrometry. In addition, a comparative study between capillary plasma samples and venous serum samples was carried out. This demonstrates the potential for the use of the described analytical system using very small amounts of blood. As internal standard (S)-(+)-alpha-amino-cyclohexane-propionic acid hydrate was used. Gabapentin and the internal standard are structural isomers, but have different m/z values for the fragments after collision induced dissolution. Gabapentin has 172-->154 and 172-->136 transitions and amino-cyclohexane-propionic acid hydrate has a 172-->126 transition which can be detected in tandem MS. Analysis of gabapentin was carried out on a C8 HPLC column using an isocratic mobile phase consisting of ammonium acetate (pH 3.0; 5mM)-methanol (96:4, v/v). The analytical method was validated for venous serum samples. Limit of detection was 1.6ng/ml and lower limit of quantification was 7.5ng/ml. R.S.D. values and bias values were within the range of acceptance for all concentration levels. The method developed for venous serum samples is being used in a gabapentin monitoring study using population pharmacokinetic modeling.


principles and practice of constraint programming | 2002

Intake of grapefruit juice alters the metabolic pattern of cyclosporin A in renal transplant recipients.

Monica Hermann; Anders Åsberg; Jan Leo Egge Reubsaet; S. Saether; Knut Joachim Berg; Hege Christensen

OBJECTIVE The aim of the present study was to investigate the effect of grapefruit juice on the pharmacokinetics of cyclosporin A (CsA), as Sandimmun Neoral, and its main metabolites, M1, M9 and M4N, in renal transplant recipients. METHODS Ten renal transplant recipients, on CsA-based immunosuppressive therapy, were included in this open, randomized crossover study. Patients were given their individualized morning dose of CsA, administered with either 250 ml water or 250 ml grapefruit juice and 12-hour CsA pharmacokinetic investigations were performed. The 2 investigation days were separated by at least 7 days. RESULTS Administration of CsA with grapefruit juice compared with water significantly increased the area under the whole blood concentration versus time curve in the interval from 0-12 hours (AUC(0-12)) of CsA, by an average of 25 +/- 19% (p = 0.002). Intake of grapefruit juice did not have any significant influence on maximum whole blood concentration (Cmax) or time to Cmax (tmax) of CsA. AUC(0-12) and Cmax of M9 decreased significantly with intake of grapefruit juice, on average 22 +/- 11% (p = 0.0007) and 36 +/- 6% (p = 0.0001), respectively. AUC(0-12) of M1, however, was on average 13 +/- 14% (p = 0.02) higher upon co-administration of CsA with grapefruit juice as compared with water. The level of M4N was below the limit of quantification in most samples, and an effect of co-administration of CsA with grapefruit juice could not be determined for this metabolite. CONCLUSION The present study shows that co-administration of grapefruit juice with CsA compared with water affects the formation and/or elimination of the 2 metabolites M1 and M9 differently. In addition, administration of CsA with grapefruit juice compared with water induced a moderate, but significant increase in systemic exposure of CsA in renal transplant recipients.


Journal of Pharmaceutical and Biomedical Analysis | 2002

Evaluation of essential parameters in the chromatographic determination of cyclosporin A and metabolites using a D-optimal design

Monica Hermann; Hege Christensen; Jan Leo Egge Reubsaet

The extensive use of routine monitoring of cyclosporin A (INN, ciclosporin) whole blood levels of patients undergoing such therapy has resulted in a wide variety of chromatographic conditions for analysing this drug. The aim of this study was to evaluate the importance of essential parameters in the chromatographic determination of cyclosporin A and its main metabolites, AM1, AM9 and AM4N. A D-optimal design was used to evaluate the effect of type and amount of organic modifier, temperature, flow rate, pH and gradient steepness. The optimal chromatographic conditions were determined by multi-linear regression. In the final chromatographic method separation of the compounds was carried out on a reversed phase C(8) column maintained at 80 degrees C. The mobile phase consisted of a linear gradient with two mobile phases containing acetonitrile and water. The flow rate was set at 0.8 ml/min. UV detection was carried out at 214 nm. Validation of the analytical method showed linearity over the range 25-1000 ng/ml (r>0.997). The detection limits of cyclosporin A, AM1, AM9 and AM4N were 1.3 pmol on column. The within-day and between-day relative standard deviations were <15% for cyclosporin A at all concentrations and for the metabolites at 250 and 1000 ng/ml, and <21% for the metabolites at limit of quantification (25 ng/ml).


Analytical and Bioanalytical Chemistry | 2005

Determination of atorvastatin and metabolites in human plasma with solid-phase extraction followed by LC–tandem MS

Monica Hermann; Hege Christensen; Jan Leo Egge Reubsaet


Nephrology Dialysis Transplantation | 2007

Cinacalcet's effect on the pharmacokinetics of tacrolimus, cyclosporine and mycophenolate in renal transplant recipients

Pål Falck; Nils Tore Vethe; Anders Åsberg; Karsten Midtvedt; Stein Bergan; Jan Leo Egge Reubsaet; Hallvard Holdaas


Journal of Chromatography B | 2007

Determination of ciclosporin A and its six main metabolites in isolated T-lymphocytes and whole blood using liquid chromatography-tandem mass spectrometry.

Pål Falck; Heidi Guldseth; Anders Åsberg; Karsten Midtvedt; Jan Leo Egge Reubsaet

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Anders Åsberg

Oslo University Hospital

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Sara Bremer

Oslo University Hospital

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Stein Bergan

Oslo University Hospital

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