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Stein Bergan

Publications and source records attributed to Stein Bergan.

9 recordsLinked to original sources
PubMed2008

Oral anticoagulation with warfarin is significantly influenced by steroids and CYP2C9 polymorphisms in children with cancer.

Clinical management of warfarin therapy is complex, and dosing algorithms do not include genetic factors or interactions with other drugs for warfarin dose determinations. We evaluated the interaction of warfarin and CYP2C9 polymorphisms and concomitant corticosteroids in 29 children with cancer. Children with heterozygous polymorphisms of CYP2C9 achieved target INR sooner and more frequently had INR above the target level, compared to children without mutations. Children on concomitant steroids had significantly lower warfarin requirements. Thus, awareness of CYP2C9 genotype and steroid-induced responsiveness to warfarin may be important when administrating oral anticoagulation in children.

Adolescent↗
PubMed2006

Determination of inosine monophosphate dehydrogenase activity in human CD4+ cells isolated from whole blood during mycophenolic acid therapy.

Inosine 5'-monophosphate dehydrogenase (IMPDH) is an established target in immunosuppression following organ transplantation. In lymphocytes, reversible inhibition of this enzyme by mycophenolic acid (MPA) results in reduced production of guanine and deoxyguanine nucleotides and thereby retarded proliferation of activated cells. In order to examine MPA pharmacodynamics in renal allograft recipients, the authors have developed an assay for the determination of IMPDH activity in CD4+ cells directly isolated from a small blood volume. Paramagnetic beads coated with anti-CD4 antibodies were utilized for the cell isolation. The intracellular MPA concentration was restored by incubating the cells in microfiltrated plasma from the original sample. Inosine 5'-monophosphate (IMP; substrate) and nicotine adenine dinucleotide (NAD; co-factor) were added to cell lysates, and IMPDH activity was quantified as the xanthosine 5'-monophosphate (XMP) production rate (pmol/10 cells/min) determined by liquid chromatography after hydrolytic cleavage to xanthine. The reaction kinetics were saturated with IMP and NAD concentrations of 1.79 micromol/L and 0.38 micromol/L, respectively. The production rate was linear in the interval 0.13 to 8.7 pmol XMP/min. Total interseries CVs based on seven replicates at each MPA concentration 0, 2.2, and 8.6 microg/mL were 25%, 16%, and 13%, respectively. When a single 1 gram mycophenolate mofetil dose was administered to a healthy individual, the measured IMPDH activity was 13% of predose value at the MPA peak concentration. The present assay allows reliable determination of IMPDH activity in CD4+ cells during MPA exposure, reducing the potential influence of sample preparation on the measured enzyme activity to a minimum. The assay may be applied to assess MPA pharmacodynamics during immunosuppressive treatment, maintaining the influence of intracellular MPA on the IMPDH activity.

CD4 Antigens↗
PubMed2006

Mycophenolic acid clinical pharmacokinetics influenced by a cyclosporine C2 based immunosuppressive regimen in renal allograft recipients.

Therapeutic drug monitoring of mycophenolic acid (MPA) in combination with cyclosporine 2-h concentration (CsA C2, n = 68) or tacrolimus trough concentration (n = 10) was investigated by repeated measurements of MPA and MPA-glucuronide (MPAG) trough concentrations in renal allograft recipients during the first 3 months post-transplant. The acute rejection rate was lower (19% vs. 43%; P < 0.05) in patients achieving CsA C2 target range during the first week (1600-2000 microg/l), n = 26, compared with those who did not, n = 42. Median MPA concentration was 0.9 and 1.2 microg/ml in patients within or below C2 range, respectively (P = 0.19). CsA C2 correlated with MPAG-to-MPA ratio (P < 0.01, r = 0.91) and gamma-glutamyl-transpeptidase (GGT, P < 0.01, r = 0.86). Total MPA concentration increased during the 3 months, but not in patients on tacrolimus. High CsA C2 lowered the acute rejection rate and plasma MPA. High CsA C2 is associated with elevated GGT, probably because of cholestatic effects, which explain the increased MPAG-to-MPA ratio. Increasing MPA concentration is ascribed to per-protocol CsA C2 reductions. In conclusion, CsA may confound the relationship between MPA and the incidence of rejection, and contribute to the difficulty of obtaining a therapeutic range for MPA in clinical practice.

Adrenal Cortex Hormones↗
PubMed2003

C2 monitoring in maintenance renal transplant recipients: is it worthwhile?

Presently, there is little knowledge regarding cyclosporine (CsA) concentration at 2 hr post-dose (C2) monitoring in maintenance patients. This study evaluates the actual C2 range in stable renal transplant recipients (who underwent transplantation >12 months ago). In addition, we investigated whether underexposure or overexposure to CsA (assessed by C2) affects graft function (as measured by serum [S]-creatinine). All renal transplant recipients in Norway receiving CsA were asked to participate; 1447 fulfilled the criteria. Valid C2 and CsA trough concentration (C0) measurements were performed in 1032 renal transplant recipients (71%) monitored by C0. Target C0 level was 75 to 125 mumol/L. CsA levels were measured using a Cloned Enzyme Donor Immunoassay method, and all analyses were performed in the same laboratory (overall mean [+/-standard deviation] CsA C0=112+/-31 mug/L, CsA C2=697+/-211 mug/L [range 81-1580 mug/L], CsA dose [mg/day]=208+/-61, CsA dose [mg/kg/day]=2.8+/-1.1, and S-creatinine=141+/-58 mumol/L). A univariate analysis of variance showed that patients with C2 levels between 700 and 800 mug/L (n=203, S-creatinine=136+/-49 mumol/L) had significantly lower S-creatinine levels compared with patients with C2 levels greater than 950 mug/L (n=94, S-creatinine=152+/-56 mumol/L) (P<0.02). The same was true for patients with C2 levels less than 450 mug/L (n=95, S-creatinine 141+/-72 mumol/L) (P<0.05) when compared with patients with C2 levels greater than 950 mug/L. There was no significant difference in S-creatinine between patients in the low and intermediate C2 group; 666 patients had C0 levels in the therapeutic range (75-125 mumol/L). A linear regression showed a significant relation between S-creatinine and C2 for these patients (P=0.03). The corresponding relation between S-creatinine and C0 was nonsignificant (P=0.3). Monitoring of C2 in maintenance patients is a valuable tool to detect overexposure to CsA. Until results from prospective studies are available, we recommend C0 in the therapeutic range and reduction in CsA in overexposed patients, aiming at a C2 value between 700 and 800 mug/L.

Adult↗
PubMed2003

Automated determination of free mycophenolic acid and its glucuronide in plasma from renal allograft recipients.

Mycophenolic acid, the active moiety of mycophenolate mofetil, inhibits the enzyme inosine monophosphate dehydrogenase. The main metabolite, mycophenolic acid glucuronide, has no immunosuppressive effect. Reported protein bindings are 97% for mycophenolic acid and 82% for mycophenolic acid glucuronide. Considerable intraindividual and interindividual variability in mycophenolic acid pharmacokinetics has been observed. Data on the variability of mycophenolic acid free fraction in plasma are sparse but may be relevant when discussing whether therapeutic drug monitoring of this drug is warranted. The authors describe a fully automated method for the determination of free concentrations by dialysis across a membrane followed by concentration of the dialysate on a trace enrichment column and liquid chromatography. Total concentrations are measured by protein precipitation and direct injection on the trace enrichment column. Plasma concentrations as low as 6 ng/mL free mycophenolic acid and 1 microg/mL free mycophenolic acid glucuronide can be measured with between-day coefficient of variation less than 15% and 6%, respectively. Stability testing confirmed that plasma samples could be stored for 14 days at 4 degrees C or -20 degrees C and at room temperature for approximately 12 hours without significant changes in free concentrations. Predose total and free concentrations of mycophenolic acid and mycophenolic acid glucuronide were determined in 27 samples from stable renal allograft recipients treated with mycophenolate mofetil, cyclosporin, and steroids. Total concentrations ranged from 0.57 to 16.2 microg/mL mycophenolic acid and 36 to 199 microg/mL mycophenolic acid glucuronide. Free concentrations ranged from 13 to 210 ng/mL mycophenolic acid and 8 to 58 microg/mL mycophenolic acid glucuronide. The method presented here has been successfully applied to measure free mycophenolic acid and free mycophenolic acid glucuronide in clinical samples. Further investigations may provide important data to support the identification of principles and target ranges for the monitoring of mycophenolic acid in the immunosuppressive therapy of organ transplant recipients.

Chromatography, High Pressure Liquid↗
PubMed2002

[Individualized pharmacotherapy based on cytochrome P-450 (CYP) genotyping].

BACKGROUND: Genetic polymorphisms of the drug-metabolising cytochrome P-450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6 have been characterized, and several of these variants lead to reduced or absent activity. This is of clinical importance mainly in patients having two non-functional alleles, phenotypically characterised as "poor metabolisers" (1-10% of Caucasians). Since most drugs are transformed into inactive or less active metabolites, "poor metabolisers" are at increased risk of developing drug induced adverse reactions. MATERIAL AND METHODS: Studies of relevant literature (MedLine search) in addition to our own experiences, show that CYP genotyping can predict the phenotype and thereby explain some abnormal drug responses and may be used to individualize pharmacotherapy. RESULTS: At present, CYP genotyping (CYP2C9/2C19/2D6) is most frequently requested in psychiatry and anticoagulant therapy, but the field is expanding. Important factors for implementation of pharmacogenetic methods are accuracy of diagnosis, quality of reports, response time, and cost. INTERPRETATION: Pharmacogenetic analyses will significantly contribute to reducing treatment costs for drug-induced adverse reactions and costs of sick leave, by predicting the best drug and the most effective and safest dosage. The expenses of full genotyping (CYP2C9/2C19/2D6) are equivalent to one day of sick leave. One might ask: Are pharmacogenetic analyses coming to the point where they drive down costs incurred by illness?

Cytochrome P-450 Enzyme System↗
PubMed2002

Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype.

OBJECTIVES: Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O-demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes. METHODS: Norwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting-curve analysis of allele-specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction-amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6-metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography-mass spectrometry. RESULTS: The pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem was > or = 5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P <.01). CONCLUSIONS: CYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N-demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.

Area Under Curve↗