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Biomedical subjects

K Brøsen

Publications and source records attributed to K Brøsen.

At least 19 recordsLinked to original sources
PubMed2004

Pharmacokinetic interaction between rifampin and the combination of indinavir and low-dose ritonavir in HIV-infected patients.

Rifampin is an important drug in the treatment of tuberculosis, but administration of rifampin in combination with protease inhibitors is complicated because of drug-drug interactions. A prospective, controlled, multiple-dose study involving 6 HIV-infected patients receiving a combination of indinavir (800 mg) and ritonavir (100 mg) twice a day was performed to evaluate whether the inducing effect of rifampin on the drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 could be overcome by the inhibitory effect of ritonavir. Pharmacokinetic evaluations of steady-state concentrations of indinavir and ritonavir were performed before and after administration of rifampin (300 mg every day for 4 days). An 87% reduction (from 837 to 112 ng/mL) in median indinavir and a 94% reduction (from 431 to 27 ng/mL) in median ritonavir concentrations were seen 12 h after the last dose of rifampin was administered (P=.031). These results strongly indicate that the administration of rifampin with a combination of indinavir (800 mg) and ritonavir (100 mg) could lead to subtherapeutic concentrations of indinavir.

Adult↗
PubMed2002

In vitro investigation of cytochrome P450-mediated metabolism of dietary flavonoids.

Human and mouse liver microsomes and membranes isolated from Escherichia coli, which expressed cytochrome P450 (CYP) 1A2, 3A4, 2C9 or 2D6, were used to investigate CYP-mediated metabolism of five selected dietary flavonoids. In human and mouse liver microsomes kaempferol, apigenin and naringenin were hydroxylated at the 3'-position to yield their corresponding analogs quercetin, luteolin and eriodictyol, whereas hesperetin and tamarixetin were demethylated at the 4'-position to yield eriodictyol and quercetin, respectively. Microsomal flavonoid metabolism was potently inhibited by the CYP1A2 inhibitors, fluvoxamine and -naphthoflavone. Recombinant CYP1A2 was capable of metabolizing all five investigated flavonoids. CYP3A4 recombinant protein did not catalyze hesperetin demethylation, but showed similar metabolic profiles for the remaining compounds, as did human microsomes and recombinant CYP1A2, although the reaction rates in general were lower as compared to CYP1A2. CYP2C9 catalyzed the 4'-demethylation of tamarixetin, whereas CYP2D6 did not seem to play any role in the metabolism of the selected flavonoids. The major involvement in flavonoid metabolism of human CYP1A2, which mediates the formation of metabolites with different biochemical properties as compared to the parent compound and furthermore is known to be expressed very differently among individuals, raises the important question of whether individual differences in the CYP enzyme activity might affect the beneficial outcome of dietary flavonoids, rendering some individuals more or less refractory to the health-promoting potential of dietary flavonoids.

Animals↗
PubMed2001

[Clozapine-induced toxic hepatitis].

A case of clozapine-induced toxic hepatitis in a 49-year old woman with schizophrenia is described. The daily clozapine dose was clinically titrated to 300 mg. Subsequently, the patient experienced lethargy and anorexia, and fever, eosinophilia, leucocytosis and abnormal liver parameters were found. The serum concentration of clozapine was 8595 nmol/l, and treatment was discontinued. After eight days, the condition stabilised, and low-dose clozapine treatment was successfully reinstituted with serum monitoring (TDM).

Chemical and Drug Induced Liver Injury↗
PubMed2001

[Tramadol and oxazepam. Effect on pulmonry function in elderly patients with chronic obstructive lung disease].

Many patients with chronic obstructive pulmonary disease (COPD) suffer from osteoporotic pain as a result of glucocorticoid treatment and nervous symptoms partly related to their lung disease. There seems to be som reluctance to treat these patients with an opioid or benzodiazepine. Upon request, the Drug Information Centre in Odense made an extensive literature search on the subject. No documentation was found that tramadol additionally depresses the respiration in patients with COPD, nor has oxazepam in clinically relevant doses been found to exacerbate their lung disease. The clinical effect is subject to large interindividual variability, and the use of these drugs should, to a greater extent, rest on experience with the individual patient. There seems to be no reason to maintain a priori this rigoristic reluctance to use tramadol and/or oxazepam in patients with COPD.

Aged↗
PubMed2001

Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram.

Citalopram is a selective serotonin reuptake inhibitor that is N-demethylated to N-desmethylcitalopram partially by CYP2C19 and partially by CYP3A4 and N-desmethylcitalopram is further N-demethylated by CYP2D6 to the likewise inactive metabolite di-desmethylcitalopram. The two metabolites are not active. The fact that citalopram is metabolised by more than one CYP means that inhibition of its biotransformation by other drugs is less likely. Besides citalopram has a wide margin of safety, so even if there was a considerable change in serum concentration then this would most likely not be of clinical importance. In vitro citalopram does not inhibit CYP or does so only very moderately. A number of studies in healthy subjects and patients have confirmed, that this also holds true in vivo. Thus no change in pharmacokinetics or only very small changes were observed when citalopram was given with CYP1A2 substrates (clozapine and therophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine and amitriptyline) and CYP3A4 (carbamazepine and triazolam). At the pharmacodynamic level there have been a few documented cases of serotonin syndrome with citalopram and moclobemide and buspirone. It is concluded that citalopram is neither the source nor the cause of clinically important drug-drug interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages.

OBJECTIVE: This review aimed to provide distinct dose recommendations for antidepressants based on the genotypes of cytochrome P450 enzymes CYP2D6 and CYP2C19. This approach may be a useful complementation to clinical monitoring and therapeutic drug monitoring. METHOD: Our literature search covered 32 antidepressants marketed in Europe, Canada, and the United States. We evaluated studies which had compared pharmacokinetic parameters of antidepressants among poor, intermediate, extensive and ultrarapid metabolizers. RESULTS: For 14 antidepressants, distinct dose recommendations for extensive, intermediate and poor metabolizers of either CYP2D6 or CYP2C19 were given. For the tricyclic antidepressants, dose reductions around 50% were generally recommended for poor metabolizers of substrates of CYP2D6 or CYP2C19, whereas differences were smaller for the selective serotonin reuptake inhibitors. CONCLUSION: We have provided preliminary average dose suggestions based on the phenotype or genotype. This is a first attempt to apply the new pharmacogenetics to suggest dose-regimens that take the differences in drug metabolic capacity into account.

Antidepressive Agents↗
PubMed2001

Fluvoxamine inhibits the CYP2C9 catalyzed biotransformation of tolbutamide.

OBJECTIVE: Our objective was to examine the interaction between fluvoxamine and tolbutamide to confirm that fluvoxamine inhibits CYP2C9. METHODS: The study was carried out as an open, randomized, crossover design with 14 healthy participants. In period A, all volunteers took 500 mg of tolbutamide orally. In period B, the volunteers were randomly assigned to one of two groups. Each group took either 150 mg or 75 mg of fluvoxamine a day for 5 days (day -3 to day 2). The groups then took 500 mg of tolbutamide as a single dose (day 0). In both periods, blood and urine were sampled at regular intervals. Plasma was analyzed for tolbutamide, and urine was analyzed for tolbutamide and its two metabolites, 4-hydroxytolbutamide and carboxytolbutamide by means of HPLC. RESULTS: During treatment with fluvoxamine, there was a statistically significant decrease in the median of the total clearance of tolbutamide, from 845 mL/h to 688 mL/h, among the volunteers who received 75 mg/d. There was a reduction that reached borderline statistical significance in the group that received 150 mg/d of tolbutamide. The clearance by means of 4-hydroxytolbutamide and carboxytolbutamide was significantly reduced in both groups (ie, from 901 mL/h to 318 mL/h in the group that received 150 mg of tolbutamide per day and from 723 mL/h to 457 mL/h in the group that received 75 mg of tolbutamide per day). Thus there was a tendency toward a more pronounced inhibition of the 4-hydroxylation during treatment with 150 mg/d of fluvoxamine compared with 75 mg/d, but the difference was not statistically significant. CONCLUSION: Fluvoxamine is a moderate inhibitor of CYP2C9 in vivo.

Adult↗
PubMed2000

[HIV protease inhibitors and interactions].

The protease inhibitors are a new class of drugs for the treatment of HIV infection. Results of treatment have proved beneficial to HIV positive patients, resulting in slower disease progression to aids and death. However the potential of drug interactions is high because of the drug-transporting P-glycoprotein and cytochrome P450 3A4-mediated metabolism. Administration of protease inhibitors may result in increased or decreased concentrations of co-administered drugs, and the plasma concentration of protease inhibitors may be affected by other drugs. It is possible to take advantage of the interactions by combining two protease inhibitors. Attention is drawn to the protease inhibitors and their possible interactions because of the advantages and disadvantages this implies. It is possible to monitor interactions by measuring plasma concentrations of the protease inhibitors.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Quinidine as a probe for CYP3A4 activity: intrasubject variability and lack of correlation with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6.

BACKGROUND: In vitro studies have shown that the formation of 3-hydroxyquinidine from quinidine is catalyzed almost exclusively by CYP3A4. In vivo this result has been supported in various interaction studies, and the use of this reaction as an in vivo biomarker reaction of CYP3A4 activity has been suggested. We studied the possible correlation of the formation clearance of 3-hydroxyquinidine with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Descriptive analyses of the outcome of various biomarker reactions were performed. METHODS: Forty-two healthy, young male volunteers participated in an open study consisting of two identical test periods separated by a 12- to 14-week washout period. In each period biomarker reactions of CYP1A2 (caffeine), CYP2C9 (tolbutamide), CYP2C19 (mephenytoin), CYP2D6 (sparteine), CYP3A4 (urinary excretion of 6beta-hydroxycortisol), as well as the pharmacokinetics of quinidine after a 200-mg single oral dose of quinidine sulfate were studied. RESULTS: The median formation clearance of 3-hydroxyquinidine were 2.40 and 2.33 L/h in the two test periods. As measured by the formation clearance of 3-hydroxyquinidine, the intraindividual coefficient of variation for CYP3A4 activity was 18%, whereas the interindividual activity varied fourfold. The formation clearance of 3-hydroxyquinidine did not correlate with the outcome of indexes for activities of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 or the urinary excretion of 6beta-hydroxycortisol. The formation clearance of 3-hydroxyquinidine correlated well to point values of 3-hydroxyquinidine to quinidine ratios in plasma and urine. CONCLUSION: The formation clearance of 3-hydroxyquinidine after a single oral dose of 200 mg quinidine sulfate may represent a useful index of CYP3A4 activity in vivo.

Adolescent↗
PubMed2000

Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding interactions of the selective serotonin reuptake inhibitors?

The selective serotonin reuptake inhibitors (SSRIs) comprise citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline and they differ from each other in chemical structure, by pharmacokinetic properties and, most importantly, with respect to enzyme-specific metabolism and interactions. Citalopram is administered as a racemic mixture. The drug is oxidated to desmethylcitalopram in the liver, partially by CYP2C19 and partially by CYP3A4. Fluoxetine is administered as a racemate of R- and S-fluoxetine. Both R- and S-fluoxetine are metabolized by CYP2D6 to the active metabolites R- and S-norfluoxetine. Fluvoxamine is metabolized to inactive metabolites by CYP1A2 and CYP2D6. Paroxetine is metabolized to inactive metabolites partially by CYP2D6, and accordingly the metabolism of paroxetine is dependent on the genetic polymorphism of CYP2D6. Sertraline is metabolized to desmethylsertraline, probably by CYP3A4. Several analytical methods have been described for all SSRIs. Most assays are based on separation by high-performance liquid chromatography or gas chromatography. Stereoselective methods for the analysis of racemic citalopram and fluoxetine have been published. The SSRIs are generally well tolerated and their therapeutic indices are large. In several studies there has not been found a clear relationship between clinical efficacy and plasma concentration, nor any threshold that defines toxic concentrations. The available data do not suggest that any benefit be obtained from routine monitoring of SSRI plasma levels. Therefore therapeutic drug monitoring (TDM) of the SSRIs may be useful mainly in situations where poor compliance is suspected and when therapeutic failure or toxic events are experienced at clinically relevant dosages. Further, in special populations, such as in elderly patients, poor metabolizers of sparteine (CYP2D6) or mephenytoin (CYP2C19), and patients with liver impairment, the measurement of plasma concentrations may be useful.

Biotransformation↗
PubMed1999

CYP2D6 polymorphism in systemic lupus erythematosus patients.

OBJECTIVES: To determine whether patients with idiopathic systemic lupus erythematosus (SLE) are associated with impaired CYP2D6 activity and to gain insight into whether there is an association between particular CYP2D6 genotypes and susceptibility to SLE, and whether CYP2D6 polymorphism is linked to any specific clinical features of SLE. METHODS: Debrisoquine sulfate (10 mg p.o.) was given to 159 healthy volunteers and 39 idiopathic SLE patients. Genotypic assay was carried out in 80 healthy volunteers and 32 patients. A 10-ml blood sample was drawn for genotypic assay. Debrisoquine and 4-hydroxydebrisoquine were determined in 8-h urine samples. Blood samples were analysed for the presence of mutations in the CYP2D6 gene, by using polymerase chain reaction (PCR) specific for CYP2D6*3 and CYP2D6*4 alleles. RESULTS: The metabolic ratio of debrisoquine to 4-hydroxydebrisoquine ranged from 0.01 to 86.98 in healthy subjects and from 0.02 to 96 in SLE patients. We observed the poor metabolizer(PM) debrisoquine phenotype in three of 39 patients with idiopathic SLE (7.6%) and five of 159 healthy subjects (3.1%). There was no significant difference in the frequency of PM phenotypes between idiopathic SLE and healthy subjects (Fisher's exact test, P = 0.19). No significant difference in the distribution of overall genotypes and allele frequencies were observed between the two groups. No significant relationships were found between specific clinical features and the overall genotype. CONCLUSION: The results of this study confirm that CYP2D6 activity is not impaired in SLE and that there is no association between SLE and phenotypic CYP2D6 status. The results also showed that there was no difference in the frequency of CYP2D6A and CYP2D6B alleles between controls and patients with SLE.

Adult↗
PubMed1999

Fluvoxamine is a potent inhibitor of tacrine metabolism in vivo.

OBJECTIVE: In vitro studies have shown that tacrine is metabolized by cytochrome P4501A2 (CYP1A2). One of the monohydroxy-metabolites has been incriminated with tacrine-induced hepatotoxicity. The aim of this study was to establish whether the potent CYP1A2 inhibitor fluvoxamine in clinically relevant doses could inhibit tacrine metabolism. METHODS: Eighteen healthy young men were enrolled in an open, randomized crossover study. In the first study period a single oral dose of tacrine 40 mg was given. In the second period the volunteers were randomized to maintenance doses of fluvoxamine 50 or 100 mg per day, and a single oral dose of tacrine 20 mg was given. RESULTS: Fluvoxamine was found to be a very potent inhibitor of tacrine metabolism. A fractional decrement in tacrine clearance of approximately 85% was found with both fluvoxamine doses, which was in good agreement with a prediction based on in vitro data. The medians of the steady-state concentration of fluvoxamine were 43 nM (range 25-49) and 70 nM (range 44-124) in the 50 mg per day and 100 mg per day groups, respectively. The steady-state concentration of fluvoxamine correlated with the fractional decrement in tacrine clearance (Spearman Rs = 0.53, P < 0.05). Modest, but statistically significant, reductions in the formation of the metabolites 1- and 2-hydroxytacrine were found during concomitant fluvoxamine treatment. CONCLUSION: Fluvoxamine at clinically relevant doses is a potent inhibitor of tacrine metabolism. This interaction is very likely to have clinical relevance. Whether concomitant fluvoxamine treatment reduces tacrine-induced hepatotoxicity needs further study.

Adult↗
PubMed1999

Effect of fluvoxamine on the pharmacokinetics of quinidine.

OBJECTIVE: To investigate the possible involvement of cytochromes CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine. METHODS: This was an open study of six healthy young male volunteers. The pharmacokinetics of a 200-mg single oral dose of quinidine were studied before and during daily treatment with 100 mg fluvoxamine. Biomarkers of other isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. RESULTS: The results showed a statistically significant median reduction of 2944% in the quinidine total apparent oral clearance, partial clearances by 3-hydroxylation and N-oxidation and residual clearance during fluvoxamine treatment. Renal clearance was unaffected by fluvoxamine. CONCLUSIONS: The effect of fluvoxamine on the formation clearances of 3-hydroxyquinidine and quinidine-N-oxide most likely reflects inhibition of cytochrome P4503A4 by fluvoxamine at clinically relevant doses. The results of this study do not rule out a possible involvement of CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine.

Anti-Arrhythmia Agents↗
PubMed1999

Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial.

It is generally believed that opioids relieve neuropathic pain less effectively than nociceptive pain and that they have no effect on some of the key characteristics of neuropathic pain such as touch-evoked pain (allodynia). Tramadol is an analgesic drug acting directly on opioid receptors and indirectly on monoaminergic receptor systems. The aim of this trial was to determine whether tramadol relieved painful polyneuropathy and reduced allodynia. The study design was randomised, double-blind, placebo-controlled and cross-over. After baseline observations, 45 patients were assigned to one of the two treatment sequences. The dose of tramadol slow-release tablets was titrated to at least 200 mg/day and at highest 400 mg/day. During the two treatment periods of 4 weeks duration, patients rated pain, paraesthesia and touch-evoked pain by use of 0-10 point numeric rating scales. Mechanical allodynia induced by stimulation with an electronic toothbrush was rated at the end of each treatment period with a similar scale. Thirty-four patients completed the study. Their ratings for pain (median 4 vs. 6, P=0.001), paraesthesia (4 vs. 6, P=0.001) and touch-evoked pain (3 vs. 5, P<0.001) were lower on tramadol than on placebo, as were their ratings of allodynia (0 vs. 4, P=0.012). The number needed to treat to obtain one patient with >/=50% pain relief was 4.3 (95% confidence interval 2.4-20). It is concluded that tramadol appears to relieve both ongoing pain symptoms and the key neuropathic pain feature allodynia in polyneuropathy.

Adult↗
PubMed1999

Cytochrome P450 and therapeutic drug monitoring with respect to clozapine.

Clozapine is an atypical antipsychotic drug that is mainly used for the treatment of refractory schizophrenia. Clozapine is eliminated by oxidation in the liver, predominantly by cytochrome P4501A2 (CYP1A2). Due to the influence of inhibitors, inducers and genetic factors on CYP1A2-activity, several studies have reported a very large interindividual variability in clozapine plasma concentrations at a fixed dose. A number of methods have been published for the measurement of clozapine and metabolites in plasma. Plasma concentrations are most frequently measured by high-performance liquid chromatography. Most methods measure clozapine and the main metabolite, norclozapine, whereas two methods measure clozapine and two metabolites. Several studies suggest that a minimum effective clozapine plasma concentration of >350 microg/l must be achieved in order to ensure acceptable clinical response, whereas the upper limit of the therapeutic interval not yet has been clearly defined. The occurrence of agranulocytosis, the most serious side-effect of clozapine treatment does not seem to be dose-related and it is not possible to predict which patients are at risk of developing agranulocytosis. The risk of central nervous system side-effects seems to increase with concentrations above 1300 microg/l. Monitoring of clozapine plasma concentrations is recommended during concomitant use of other drugs that are known to interact with the oxidation of clozapine, such as carbamazepine (inducer) or fluvoxamine (inhibitor). Overall, it is concluded that therapeutic drug monitoring may be of value in the clinical management of clozapine.

Antipsychotic Agents↗