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Biomedical subjects

L Bertilsson

Publications and source records attributed to L Bertilsson.

At least 19 recordsLinked to original sources
PubMed2005

Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists.

BACKGROUND: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear. OBJECTIVE: To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA. METHODS: A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53,067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed. RESULTS: Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas. CONCLUSION: Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk.

Adolescent↗
PubMed2005

Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists.

BACKGROUND: Existing studies of solid cancers in rheumatoid arthritis (RA) reflect cancer morbidity up until the early 1990s in prevalent cohorts admitted to hospital during the 1980s. OBJECTIVE: To depict the cancer pattern of contemporary patients with RA, from updated risk data from prevalent and incident RA populations. To understand the risk of solid cancer after tumour necrosis factor (TNF) treatment by obtaining cancer data from cohorts treated in routine care rather than trials. METHODS: A population based study of three RA cohorts (one prevalent, admitted to hospital 1990-2003 (n = 53,067), one incident, diagnosed 1995-2003 (n = 3703), and one treated with TNF antagonists 1999-2003 (n = 4160)), which were linked with Swedish nationwide cancer and census registers and followed up for cancer occurrence through 2003. RESULTS: With 3379 observed cancers, the prevalent RA cohort was at marginally increased overall risk of solid cancer, with 20-50% increased risks for smoke related cancers and +70% increased risk for non-melanoma skin cancer, but decreased risk for breast (-20%) and colorectal cancer (-25%). With 138 cancers, the incident RA cohort displayed a similar cancer pattern apart from non-decreased risks for colorectal cancer. TNF antagonist treated patients displayed solid cancer (n = 67) risks largely similar to those of other patients with RA. CONCLUSION: The cancer pattern in patients treated with TNF antagonists mirrors those of other contemporary as well as historic RA cohorts. The consistent increase in smoking associated cancers in patients with RA emphasises the potential for smoking cessation as a cancer preventive measure in RA.

Adolescent↗
PubMed2004

Results from a nationwide postmarketing cohort study of patients in Sweden treated with etanercept.

OBJECTIVES: To describe a nationwide system for postmarketing follow up of new antirheumatic drugs in Sweden, and to analyse safety and effectiveness in an etanercept treated patient cohort. METHODS: Etanercept became available in Sweden for prescribing on a named patient basis in 1999. All patients treated were included in a follow up of intensified adverse event reporting and recording of clinical outcome during 24 months, according to the EULAR core set. RESULTS: The mean (SD) disease activity score (DAS 28) value at inclusion among 820 patients recruited on a named patient basis during year 1 was 5.99 (1.19). After two years, 21% (n = 172) of these patients had discontinued the treatment. Of the remaining 648 patients, 68% (n = 442) responded to the treatment. However, in 55% of the responders, the disease activity was intermediate or high (mean DAS 28, 3.37 (1.20)). In all, 540 adverse events were reported in 421 adverse drug reaction (ADR) reports, in 294 patients. The events in 80 reports (19%) were serious. Twenty two per cent of the events were infections, of which 24% (n = 29) were serious. The incidence of serious adverse events remained constant over time. CONCLUSIONS: At start of etanercept treatment, patients had high disease activity. Activity remained high in a large proportion of the responding patients. Although serious ADRs occurred during late phases of treatment, no unexpected safety problems arose. No specific indicators of ADR risk were found. The monitoring system that was established may be useful in future postmarketing surveillance.

Adult↗
PubMed2003

Disposition of debrisoquine and nortriptyline in Korean subjects in relation to CYP2D6 genotypes, and comparison with Caucasians.

AIMS: To study the influence of the CYP2D6*10 allele on the disposition of debrisoquine and nortriptyline. METHODS: The pharmacokinetics of debrisoquine and nortriptyline and their main metabolites were determined in ten Koreans with the CYP2D6*1/*1 (n = 5) and CYP2D6*1/*10 (n = 5) genotypes after single oral doses of 20 mg debrisoquine and 25 mg nortriptyline, respectively. The data were compared with previously published findings from 21 Caucasians with 0, one, two, three, four or 13 functional CYP2D6 genes. RESULTS: The AUC0-8 of 4-hydroxydebrisoquine was significantly lower in Koreans with CYP2D6*1/*10 genotype compared with CYP2D6*1/*1[95% confidence interval (CI) for the ratio between means 1.17, 1.85]. No other genotype-related differences were found in the plasma kinetics of nortriptyline and debrisoquine, or their hydroxy metabolites. The AUCnortriptyline/AUC10-hydroxynortriptyline ratio did not differ between the *1/*1 and *1/*10 genotype groups (95% CI for the ratio of means 0.60, 1.26). Similarly, there was no difference between these genotypes with respect to the AUCdebrisoquine/AUC4-hydroxydebrisoquine ratio (95% CI for the ratio of mean values 0.38, 1.46). Both Korean genotype groups had similar AUCs and parent compound/metabolite AUC ratios of debrisoquine and nortriptyline to Caucasians with two functional CYP2D6 genes. CONCLUSIONS: Heterozygosity for CYP2D6*10 decreases the CYP2D6-dependent elimination of nortriptyline and debrisoquine to only a limited degree. Further studies in subjects homozygous for CYP2D6*10 are required to elucidate fully the pharmacokinetic consequences of this CYP2D6 genotype in Orientals.

Adult↗
PubMed2003

Individualized medicine - implementation of pharmacogenetic diagnostics in antidepressant drug treatment of major depressive disorders.

Antidepressant drug therapy is characterized by a high rate of therapeutic failure. There is increasing evidence that genetic factors are contributing to the inter-individual variability in antidepressant drug response. Genetic variability is described in both the pharmacokinetic part of drug action as well as in pharmacodynamic structures mediating drug effects. Genetic polymorphisms in drug metabolizing enzymes are well characterized and have large effects on oral clearances or elimination half-lives of antidepressant drugs. These differences can be compensated by adapting the individual dose to genotype in addition to other factors such as gender, weight, age, liver and kidney function. On the part of drug action, genetic variability is described in molecular structures of antidepressant effects. Several studies on response of antidepressants have revealed influences of polymorphisms in neurotransmitter receptors and transporters changing sensitivity of patients to treatment with antidepressants; however, results were often contradictory. A pharmacogenomic approach to individualize antidepressant drug treatment is recommended to be based on several levels: 1) identifying and validating the candidate genes involved in drug-response; 2) providing therapeutic guidelines; and 3) developing a pharmacogenetic test-system for bedside-genotyping.

Age Factors↗
PubMed2002

Does hepatic metabolism of melatonin affect the endogenous serum melatonin level in man?

Melatonin (MT) is metabolized in the liver by cytochrome P450 (CYP) 1A2 but its importance for the metabolic process has not been fully elucidated. Therefore, the objective of this investigation was to study whether patients with different CYP1A2 activity would have different nocturnal serum MT levels. For that purpose serum MT concentrations were determined every second hour during the night in 12 healthy subjects and their MT areas under the curve (MT-AUCs) were calculated. Caffeine (CA) clearance was determined in advance. It is generally accepted that CA clearance reflects CYP1A2 activity. This made it possible to evaluate whether a relationship prevails between endogenous MT-AUCs and CYP1A2 activity. If CYP1A2 is of importance for the metabolism of MT one would expect to find an inverse correlation between the MT-AUCs and the CA clearance. However, such correlation did not exist in the current study (Rs=-0.021, NS). Since endogenous MT-AUC is dependent not only on MT elimination by CYP1A2 but also on MT secretion, it is possible that an increased MT secretion counter-balances an increased hepatic MT metabolism. If so, this could explain why the MT-AUCs and the CA clearance values were not inversely correlated in this study.

Adult↗
PubMed2002

The single nucleotide polymorphism T1128C in the signal peptide of neuropeptide Y (NPY) was not identified in a Korean population.

OBJECTIVE: A single nucleotide polymorphism (SNP) T1128C, which causes an amino acid change from leucine(7) to proline(7) in the signal peptide of neuropeptide Y (NPY), has been found to be associated with multiple clinical parameters or disease. However, this SNP was not identified in the Japanese population. We asked if this is also true in the Korean population. METHODS: Genotyping was conducted by pyrosequencing, a newly developed real-time high-throughput SNP scoring technique. RESULTS: All 242 Korean subjects showed T1128/T1128 genotype. CONCLUSIONS: The T1128C SNP does not appear to exist in this Korean population.

Adult↗
PubMed2001

Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4.

The major cholesterol oxidation products in the human circulation are 27-hydroxycholesterol, 24-hydroxycholesterol, and 7alpha-hydroxycholesterol. These oxysterols are formed from cholesterol by specific cytochrome P450 enzymes, CYP27, CYP46, and CYP7A, respectively. An additional oxysterol present in concentrations comparable with 7alpha- and 24-hydroxycholesterol is 4beta-hydroxycholesterol. We now report that patients treated with the antiepileptic drugs phenobarbital, carbamazepine, or phenytoin have highly elevated levels of plasma 4beta-hydroxycholesterol. When patients with uncomplicated cholesterol gallstone disease were treated with ursodeoxycholic acid, plasma 4beta-hydroxycholesterol increased by 45%. Ursodeoxycholic acid, as well as the antiepileptic drugs, are known to induce cytochrome P450 3A. Recombinant CYP3A4 was shown to convert cholesterol to 4beta-hydroxycholesterol, whereas no conversion was observed with CYP1A2, CYP2C9, or CYP2B6. The concentration of 4alpha-hydroxycholesterol in plasma was lower than the concentration of 4beta-hydroxycholesterol and not affected by treatment with the antiepileptic drugs or ursodeoxycholic acid. Together, these data suggest that 4beta-hydroxycholesterol in human circulation is formed by a cytochrome P450 enzyme.

Adult↗
PubMed2001

CYP2C19 polymorphism is not important for the in vivo metabolism of selegiline.

OBJECTIVES: To address the relevance of cytochrome P-450 (CYP) 2C19 polymorphism for the pharmacokinetics and dynamics of selegiline and its two known primary metabolites, desmethylselegiline and l-methamphetamine. METHODS: Six extensive (mephenytoin S/R ratio < 0.3; EM) and six poor (mephenytoin S/R ratio > 0.8; PM) hydroxylators of S-mephenytoin ingested a single 10-mg oral dose of selegiline hydrochloride. Serum concentrations of selegiline, desmethylselegiline and l-methamphetamine were measured by gas chromatography--mass spectrometry for up to 48 h. In addition, the platelet monoamine oxidase type B (MAO-B) activity was measured for 14 days to describe possible differences in the pharmacodynamics of selegiline and its metabolites between EM and PM. RESULTS: The CYP2C19 phenotype had no significant effects on the pharmacokinetic variables of selegiline. PM of S-mephenytoin had 68% higher mean AUC of desmethylselegiline (P = 0.0017) than EM, but no significant differences were observed in other pharmacokinetic parameters of desmethylselegiline. Contrary to desmethylselegiline, the serum l-methamphetamine concentrations were slightly lower in PM, but no statistically significant differences were observed in l-methamphetamine pharmacokinetics between the two CYP2C19 phenotypes. Accordingly, the magnitude of MAO-B inhibition showed no significant differences between the study groups. CONCLUSIONS: CYP2C19 polymorphism does not seem to be crucial for the metabolism or clinical effects of selegiline.

Adult↗
PubMed2001

Risperidone metabolism in relation to CYP2D6*10 allele in Korean schizophrenic patients.

OBJECTIVE: Risperidone is known to be biotransformed to its active metabolite, 9-hydroxyrisperidone, by the polymorphic CYP2D6 in Caucasians. This study aimed to investigate the relationship between the CYP2D6*10 allele and the plasma levels of risperidone and 9-hydroxyrisperidone in Korean schizophrenic patients. METHODS: Eighty-two Korean schizophrenic patients in monotherapy with oral doses of risperidone from 1 mg/day to 8 mg/day (mean +/- SD 4.3 +/- 1.9, median 4) participated in this study. Plasma concentrations of risperidone and 9-hydroxyrisperidone were analyzed using high-performance liquid chromatography. The CYP2D6*10 allele, which contains C188T mutation in exon 1, was identified using allele-specific polymerase chain reaction amplification. RESULTS: Seventeen of 82 patients were homozygous for CYP2D6*1, 22 for *10, while the remaining 43 patients were heterozygous for these alleles. The plasma levels of risperidone and 9-hydroxyrisperidone ranged from 1.0 nM to 168 nM and 6.2 nM to 235 nM, respectively. The median concentrations/dose (C/Ds) (range) of risperidone in CYP2D6*1/*1, *1/*10, and *10/*10 groups were 1.7 (0.2-7.9), 2.6 (0.3-27.1), and 6.7 nM/mg (2.4-21.0), respectively. There was a statistically significant difference among the three genotypes (Kruskal-Wallis test, P<0.001). For 9-hydroxyriperidone, the corresponding median C/Ds were 13.1 (3.3-25.4), 11.9 (4.2-30.8), and 13.6 nM/mg (6.5-52.8), respectively, with no significant difference between the genotypes (P=0.54). The medians of the ratios between risperidone and 9-hydroxyrisperidone concentrations were 0.13 (0.01-0.93), 0.28 (0.01-2.77), and 0.46 nM/mg (0.05-1.28) in *1/*1, *1/*10, and *10/*10 genotypes, respectively, and they were significantly different (P=0.004). The active moieties (sum of the C/Ds of risperidone and 9-hydroxyrisperidone) were not significantly different between the genotypes (P=0.063). CONCLUSION: In Korean schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6, and the CYP2D6*10 allele is important for the regulation of the activity of this enzyme. There were no significant differences in the plasma concentration of parent drug plus its active metabolite between the genotypes. This suggests that the clinical significance of this polymorphism is limited. Our study confirms previous studies on risperidone metabolism in Caucasians.

Adolescent↗
PubMed2001

Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients.

AIMS: This study was carried out to evaluate the influence of CYP2D6 genotype on the steady state plasma concentrations of haloperidol and reduced haloperidol in Korean schizophrenic patients. METHODS: One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3-60, median 20 mg day-1) during monotherapy were recruited. CYP2D6 genotypes were determined by analysis of the CYP2D6*10 allele using allele-specific PCR and the CYP2D6*5 allele by long-PCR. Steady state plasma concentrations of haloperidol and reduced haloperidol were analysed by h.p.l.c. RESULTS: Twenty-three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patients (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/*5, respectively. The allele frequencies of CYP2D6*1, *10 and *5 were 44.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r2 = 0.60, P < 0.0001) and reduced haloperidol (quadratic equation; r(2) = 0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups (one-way ANOVA; P = 0.028). No significant differences between the genotype groups were found with respect to the C/D of reduced haloperidol (P = 0.755). However, in patients with daily doses less than 20 mg, significant differences in the C/D of haloperidol (P = 0.003), but not of reduced haloperidol, were found between the three major genotype groups. In patients with doses higher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropine, an antimuscarinic agent. All four patients with a *5 allele (one together with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patients with one or two mutated alleles (Fisher's exact test; P = 0.036). CONCLUSIONS: The dose-corrected steady state plasma concentrations of haloperidol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (< 20 mg daily), while another enzyme, probably CYP3A4, contributes at higher doses.

Adult↗
PubMed2001

Orally given melatonin may serve as a probe drug for cytochrome P450 1A2 activity in vivo: a pilot study.

BACKGROUND: Melatonin is a hormone that is metabolized by cytochrome P450 (CYP) 1A2 to its main primary metabolite 6-hydroxymelatonin. We therefore evaluated the utility of oral melatonin as a marker of hepatic CYP1A2 activity. METHODS: Twenty-five milligrams of melatonin was given at 9:30 am to 12 healthy Swedish volunteers, who had previously been phenotyped for CYP1A2 with caffeine. Melatonin and conjugated 6-hydroxymelatonin were analyzed by liquid chromatography-mass spectrometry in blood samples taken between 0.5 and 6.5 hours after drug intake. Serum concentrations of melatonin and conjugated 6-hydroxymelatonin, or their ratio at different time points, and the apparent melatonin clearance were tested for correlation with caffeine clearance. RESULTS: We found a significant correlation between apparent clearance of melatonin and caffeine clearance with a Spearman rank correlation coefficient (Rs) of 0.75 (P =.005). The melatonin concentration 1.5 hours after administration also closely correlated with the caffeine clearance (Rs = -0.62; P =.03). Inclusion of conjugated 6-hydroxymelatonin gave no closer correlations. CONCLUSION: Melatonin might be developed as an alternative to caffeine as a probe drug for CYP1A2 phenotyping.

Administration, Oral↗
PubMed2001

Determination of exogenous melatonin and its 6-hydroxy metabolite in human plasma by liquid chromatography-mass spectrometry.

SUMMARY: Melatonin has recently garnered interest as a possible treatment for sleep disorders, and this has created a desire for appropriate pharmacokinetic studies. No method has yet been published that can measure the concentrations of both melatonin and its main metabolite, 6-hydroxymelatonin, in plasma or serum. Therefore, a liquid chromatography-mass spectrometry (LC/MS) method including enzymatic hydrolysis and one-step liquid-liquid extraction was developed for this purpose. The mean extraction recovery was 59% for melatonin and 42% for 6-hydroxymelatonin. The mean precision of the method as calculated from the interassay coefficient of variation of quality control samples at high and low concentrations was 18% for 6-hydroxymelatonin and 15% for melatonin. The inaccuracy was always less than 2%. The limit of detection was approximately 2 ng/mL for 6-hydroxymelatonin (signal/noise ratio = 4) and less than 2 ng/mL for melatonin (signal/noise ratio at 2 ng/mL = 10). The method was applied to the analysis of plasma from a healthy volunteer who had received a single oral dose of 25 mg melatonin.

Chromatography, Liquid↗
PubMed2001

Characterization of the CYP2D6*29 allele commonly present in a black Tanzanian population causing reduced catalytic activity.

Debrisoquine metabolism among Tanzanians has been found to be slower than expected from the CYP2D6 genotype. In order to evaluate any genetic explanation, the coding sequence and intron-exon boundaries of the CYP2D6 gene from three Black Tanzanian volunteers with a CYP2D6*1/*1 or CYP2D6*2/*2 genotype and debrisoquine metabolic ratios (MRs) > 1 were fully sequenced to screen for new mutations. Two functional mutations, G1747 to A (causing V136I) and G3271 to A (causing V338M), were identified in the CYP2D6*2/*2 sample. Thirty-six subjects (34%) out of a total 106 subjects were heterozygous and three subjects (3%) were homozygous for the allele, yielding an allele frequency of 20%. The CYP2D6*29 allele, having also the mutations of the CYP2D6*2 allele, was subsequently expressed in yeast and mammalian COS-1 cells. No differences were seen with respect to the affinity (Km) or maximal velocity (Vmax) of the CYP2D6 substrate bufuralol between the wild-type and mutant when expression was carried out in yeast cells. By contrast, the 1'-hydroxybufuralol catalytic activity of the mutant expressed in COS-1 cells was only 26% of the wild-type (P < 0.01; Mann-Whitney U-test) and its debrisoquine hydroxylation activity was 63% of that of CYP2D6.1. The single mutants V136I and V338M had reduced capacity for bufuralol hydroxylation, but the effect was even stronger when both mutations were present together as in CYP2D6.29. Analysis of the distribution of CYP2D6*29 in subjects phenotyped for debrisoquine revealed that this allele significantly causes a reduction in the rate of debrisoquine hydroxylation in vivo. The results indicate the common existence in Tanzanians of a variant CYP2D6 form with different substrate specificity as compared to the wild-type form of the enzyme causing reduced capacity for debrisoquine metabolism.

Alleles↗
PubMed2001

Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test.

BACKGROUND: The ultrarapid metabolizer phenotype of the cytochrome P4502D6 (CYP2D6) enzyme has been considered a relevant cause of nonresponse to antidepressant drug therapy. Prescribing high doses of antidepressants to such patients leads to high concentrations of potentially toxic metabolites and an increased risk for adverse reactions. Normalization of the metabolic status of ultrarapid metabolizers by inhibition of CYP2D6 activity could offer a clinically acceptable method to successfully treat such patients with antidepressants. METHODS: Five ultrarapid metabolizers with a CYP2D6 gene duplication or triplication were treated with 25 mg nortriptyline twice a day for 3 consecutive weeks, alone during the first week and concomitantly with the CYP2D6 inhibitor paroxetine 10 mg or 20 mg twice a day, respectively, during the second and third weeks. After the third week, nortriptyline was discontinued and the subjects were treated with paroxetine 20 mg twice a day during the fourth study week. At the end of each study week, the steady-state pharmacokinetic parameters of nortriptyline or paroxetine were determined within the dose interval. In addition, the CYP2D6 phenotype was determined by debrisoquin (INN, debrisoquine) test at baseline and at the end of each study phase. Treatment-related adverse events were recorded during drug administration and for 1 week thereafter. RESULTS: All 5 subjects had very low (subtherapeutic) nortriptyline concentrations after 7 days' treatment with nortriptyline only. Addition of paroxetine 10 mg twice a day to the nortriptyline regimen resulted in a change in all individuals to the "normal" extensive debrisoquine metabolizer phenotype, and therapeutic plasma nortriptyline concentrations were achieved in 4 of 5 subjects after a 3 times mean increase in nortriptyline trough concentration (P =.0011). Doubling the paroxetine dose caused a 15 times mean increase in paroxetine trough concentration (P <.001), indicating strong inhibition by paroxetine of its own metabolism. The high paroxetine concentrations in 2 subjects caused them to have the poor debrisoquine metabolizer phenotype and resulted in a further increase in plasma nortriptyline trough concentration (P =.0099). A strong correlation (rank correlation coefficient [r(s)] = 0.89; P <.0001) was observed between paroxetine and nortriptyline trough concentrations. Paroxetine also significantly decreased the fluctuation of nortriptyline concentrations within the dose interval. One subject discontinued the study after the second study week because of adverse effects; otherwise, the study drugs were well tolerated. CONCLUSIONS: Paroxetine, with a daily dosage from 20 to 40 mg, is an effective tool in normalizing the metabolic status of CYP2D6 ultrarapid metabolizers.

Adult↗
PubMed2000

CYP2D6 genotype and antipsychotic-induced extrapyramidal side effects in schizophrenic patients.

OBJECTIVE: In order to evaluate whether poor metabolizers (PM) of debrisoquine are overrepresented among patients with acute dystonic reactions and chronic movement disorders associated with the administration of antipsychotic drugs, the CYP2D6 genotype was determined in schizophrenic patients. METHODS: Allele status for CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 as well as gene duplication was determined by allele-specific PCR, long-PCR and restriction fragment length polymorphism analysis (RFLP) in 119 schizophrenic patients (99 males and 20 females). All subjects were treated with antipsychotics metabolized, at least partially, by this isozyme. Sixty-three of the patients (52.9%) had a history of extrapyramidal side effects (EPS), while 56 (47.1%) had not experienced such problems (controls). RESULTS: Sixty-five patients (54.6%) were homozygous for a functional CYP2D6*1 allele, 44 (37.0%) were heterozygous for detrimental alleles, and 4 (3.4%), who carried two detrimental alleles, were classified as PM. In six patients (5.0%) duplication of a functional CYP2D6 gene was found, and they were consequently classified as ultrarapid metabolizers (UM). Homo- and heterozygous extensive metabolizers (EM) as well as UM were equally distributed between patients with and without EPS, whereas all the PM had a history of EPS. No significant differences in allele frequencies between the two groups were found. CONCLUSION: Although the results cannot be considered conclusive due to the small number of PM patients in our study, the PM genotype may be a predisposing factor for antipsychotic-induced EPS. Knowledge of the CYP2D6 genotype, before starting antipsychotic therapy, might be useful in identifying subjects at risk of developing EPS.

Adult↗
PubMed2000

Fluvoxamine but not citalopram increases serum melatonin in healthy subjects-- an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin.

OBJECTIVE: The nocturnal serum melatonin (MT) level increases after ingestion of fluvoxamine (FLU)-- a selective serotonin re-uptake inhibitor (SSRI) with antidepressive properties. The mechanism behind the MT increase is unknown. Citalopram (CIT) is another SSRI. It is not known whether CIT affects the serum MT level. It may well be that these two compounds affect serum MT levels differently, inasmuch as the ways they inhibit cytochrome P450 (CYP) enzymes in the liver differ markedly. FLU inhibits CYP1A2 potently, and to some extent also CYP2C19, whereas CIT is without such an effect. CYP enzymes are probably involved in the hepatic metabolism of MT. If FLU, but not CIT, inhibits liver enzymes involved in the metabolism of MT, different serum MT concentrations should probably ensue. The objective of this investigation was to test this hypothesis. METHODS: Seven healthy subjects participated in three different experiments, which were performed in random order 6-8 days apart. In experiment A, placebo was given, in experiment B 40 mg CIT and in experiment C 50 mg FLU. All doses were given orally at 1600 hours. Serum MT concentrations were determined at regular intervals between 1600 hours and noon next day (20 h). Plasma concentrations of CIT were measured repeatedly in experiment B, and plasma FLU concentrations in experiment C. MT areas under the curve representing the 20-h period (MT-AUC(0-20)) were compared in the three experiments, and differences were statistically evaluated. RESULTS: FLU augmented the MT-AUC(0-20) by a factor of 2.8 compared with the effect of placebo (P < 0.01), whereas CIT was without significant effect. More MT was excreted in the urine after ingestion of FLU than after placebo. In contrast, CIT did not influence the MT excretion. A clear relationship was found between serum levels of MT and plasma concentrations of FLU. CONCLUSION: The serum MT level increased markedly after ingestion of FLU but not after CIT. The exact mechanism behind this finding is unknown, but decreased hepatic metabolism of MT by either CYP1A2 or CYP2C19, or both, is probable. Although exogenous MT, causing high MT concentration in plasma, has sleep-promoting properties in man, it is at this stage unknown whether serum MT concentrations in the range found in this study have similar effects. This has to be given further attention in additional studies.

Administration, Oral↗