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Leif Bertilsson - One of the best experts on this subject based on the ideXlab platform.
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a novel mutant variant of the cyp2d6 gene cyp2d617 common in a black african population association with diminished Debrisoquine hydroxylase activity
British Journal of Clinical Pharmacology, 2003Co-Authors: Collen Masimirembwa, Leif Bertilsson, Julia A Hasler, Irene Persson, Magnus IngelmansundbergAbstract:1. The Debrisoquine hydroxylase (CYP2D6) is polymorphically distributed. Not only are there differences in the proportions of extensive metabolisers to poor metabolisers in various ethnic groups, but there are also pronounced variations in the metabolic capacity among those classified as extensive metabolisers. 2. The mean Debrisoquine metabolic ratio of Caucasian extensive metabolisers is lower than that for a number of African populations. In the present study, we have searched for novel CYP2D6 mutations to explain the diminished enzyme activity in African populations. 3. Three Zimbabwean Shona subjects with EM phenotypes (metabolic ratios for Debrisoquine of 0.4, 1.5 and 10.5 respectively) were selected and the open reading frame of the CYP2D6 gene of each was sequenced. 4. The subject with metabolic ratio of 10.5 was found to be homozygous for an allele with a nucleotide exchange in exon 2, 1111C-->T causing a 107Thr-->Ile amino acid exchange in a conserved region of the enzyme. In addition, he was homozygous for the 2938C-->T and 4268G-->C mutations causing 296Arg-->Ser and 486Ser-->Thr amino acid substitution found in the CYP2D6*2 allele. 5. Seventy-six Zimbabwean Shona subjects were subsequently genotyped for the 1111C-->T mutation and for the intron 1 gene conversion present in the CYP2D6*2 gene. The 1111C-->T mutation was found at an allele frequency of 34% and was only present in alleles carrying the gene conversion in intron 1 indicative for the CYP2D6*2 gene. 6. This allele (CYP2D6*17), containing the 1111C-->T, 2938C-->T and 4268G-->C mutations, was found to be strongly associated with lower capacity for Debrisoquine hydroxylation. We therefore postulate that the CYP2D6*17 allele might contribute to the molecular basis of the previously established diminished Debrisoquine hydroxylase activity in African Bantu populations.
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involvement of cyp2d6 but not cyp2c19 in nicergoline metabolism in humans
British Journal of Clinical Pharmacology, 2003Co-Authors: Ylva Bottiger, Gunnar Alvan, P Dostert, Strolin M Benedetti, M Bani, F Fiorentini, M Casati, I Poggesti, C Alm, Leif BertilssonAbstract:1. Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia. 2. Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-alpha-methoxy-9,10-dihydrolysergol (MMDL), which is further N-demethylated to form 10-alpha-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the Debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms. 3. After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their Debrisoquine and S-mephenytoin hydroxylation phenotypes. 4. The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of Debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL Cmax 59 nmol l-1 and AUC (0, th) 144 nmol l-1h, mean MDL Cmax 183 nmol l-1 and AUC 2627 nmol l-1h) but were markedly different from the five subjects who were poor metabolisers of Debrisoquine (mean MMDL Cmax 356 nmol l-1 and AUC 10512 nmol l-1h, MDL concentrations below limit of quantitation). 5. We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the Debrisoquine hydroxylation polymorphism.
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disposition of Debrisoquine and nortriptyline in korean subjects in relation to cyp2d6 genotypes and comparison with caucasians
British Journal of Clinical Pharmacology, 2003Co-Authors: Per Dalen, Gunnel Tybring, Marja-liisa Dahl, Grant R. Wilkinson, Michel Eichelbaum, Hk Roh, Leif BertilssonAbstract: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.
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disposition of Debrisoquine in caucasians with different cyp2d6 genotypes including those with multiple genes
Pharmacogenetics, 1999Co-Authors: Per Dalen, Marja-liisa Dahl, Leif Bertilsson, Michel Eichelbaum, Grant R. WilkinsonAbstract:Debrisoquine is a major prototypic in-vivo probe used to assess polymorphic CYP2D6 activity in humans, based on the 0-8 h urinary excretion of unchanged drug and its 4-hydroxy metabolite (the so-called metabolic ratio). The primary purpose of the study was to investigate further the relationship between genotype and phenotype by determining the overall disposition characteristics of the drug in selected groups of healthy Swedish Caucasian individuals. Debrisoquine (20 mg) was orally administered to five poor metabolizers with no functional CYP2D6 gene, five heterozygous extensive metabolizers, five homozygous extensive metabolizers, five ultrarapid metabolizers with duplicated/triplicated CYP2D6*2 genes and one individual with 13 copies of CYP2D6*2. Peak plasma levels of Debrisoquine and 4-hydroxyDebrisoquine were attained within 2-4 h and then declined in a multi-exponential fashion over 96 h. However, the post 8-h period of the elimination process was characterized by irregular fluctuations that prevented formal pharmacokinetic analysis. Nevertheless, marked differences were apparent in the compounds' plasma level-time profiles between the CYP2D6 genotypes. For example, in the case of Debrisoquine, the mean ratio of the AUC(0-8) values was 22:22:7:6:1, corresponding to 0, 1, 2, 3/4 and 13 genes and, for 4-hydroxyDebrisoquine, the respective values were 1:7:19:28:17. The 0-96 h urinary recovery of Debrisoquine differed 100-fold between the genotypes, being essentially complete in poor metabolizers and zero in the individual with 13 CYP2D6*2 genes. 4-hydroxyDebrisoquine excretion increased according to the number of functional CYP2D6 genes. A highly significant correlation (r(s) = 0.95, P < 0.001) was observed between the plasma AUC(0-8) ratio for Debrisoquine to 4-hydroxyDebrisoquine and the 0-8 h urinary metabolic ratio. This study demonstrates that the number of functional CYP2D6 alleles is critically important in the plasma concentration-time curves of Debrisoquine and its CYP2D6-mediated 4-hydroxy metabolite. Concentration-related pharmacologic effects would be expected to be similarly affected by gene dosage and it is likely that the same situation also applies to other drugs whose elimination is importantly determined by this enzyme; for example, many antidepressants and neuroleptics, antiarrhythmic agents, beta-adrenoceptor antagonists and opiates.
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decreased capacity for Debrisoquine metabolism among black tanzanians analyses of the cyp2d6 genotype and phenotype
Pharmacogenetics, 1999Co-Authors: Agneta Wennerholm, Marja-liisa Dahl, Leif Bertilsson, Inger Johansson, Magnus Ingelmansundberg, Christina Alm, Amos Y Massele, Mary Jande, Yakoub Adenabdi, Lars L GustafssonAbstract:The cytochrome P450 2D6 (CYP2D6) genotypes and phenotypes of 106 unrelated, healthy black Tanzanians of Bantu origin were investigated. The results revealed a population with a generally decreased capacity to metabolize the CYP2D6 substrate Debrisoquine with 59% of the Tanzanian extensive metabolise
Marja-liisa Dahl - One of the best experts on this subject based on the ideXlab platform.
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lack of effect of chloroquine on the Debrisoquine cyp2d6 and s mephenytoin cyp2c19 hydroxylation phenotypes
British Journal of Clinical Pharmacology, 2003Co-Authors: Collen Masimirembwa, Marja-liisa Dahl, Lars L Gustafsson, Yakoub Aden Abdi, Julia A HaslerAbstract:The effects of chloroquine (CHQ) on Debrisoquine hydroxylase (CYP2D6) and S-mephenytoin hydroxylase (CYP2C19) were assessed in 11 black Zimbabwean and 12 white Swedish healthy volunteers. The activity of CYP2D6 was measured as the urinary Debrisoquine to 4-hydroxyDebrisoquine metabolic ratio and that of CYP2C19 as the urinary S- to R-mephenytoin enantiomer ratio (S/R). There were no statistically significant differences in either metabolic ratio as a result of prophylactic or loading doses of CHQ. This indicates that CHQ does not inhibit CYP2D6 or CYP2C19 in vivo and is unlikely to compromise the metabolism of substrates for these two enzymes. It is, therefore, also unlikely that residual CHQ in populations under study will interfere with phenotyping of either CYP2D6 or CYP2C19.
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disposition of Debrisoquine and nortriptyline in korean subjects in relation to cyp2d6 genotypes and comparison with caucasians
British Journal of Clinical Pharmacology, 2003Co-Authors: Per Dalen, Gunnel Tybring, Marja-liisa Dahl, Grant R. Wilkinson, Michel Eichelbaum, Hk Roh, Leif BertilssonAbstract: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.
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decreased capacity for Debrisoquine metabolism among black tanzanians analyses of the cyp2d6 genotype and phenotype
Pharmacogenetics, 1999Co-Authors: Agneta Wennerholm, Marja-liisa Dahl, Leif Bertilsson, Inger Johansson, Magnus Ingelmansundberg, Christina Alm, Amos Y Massele, Mary Jande, Yakoub Adenabdi, Lars L GustafssonAbstract:The cytochrome P450 2D6 (CYP2D6) genotypes and phenotypes of 106 unrelated, healthy black Tanzanians of Bantu origin were investigated. The results revealed a population with a generally decreased capacity to metabolize the CYP2D6 substrate Debrisoquine with 59% of the Tanzanian extensive metabolise
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disposition of Debrisoquine in caucasians with different cyp2d6 genotypes including those with multiple genes
Pharmacogenetics, 1999Co-Authors: Per Dalen, Marja-liisa Dahl, Leif Bertilsson, Michel Eichelbaum, Grant R. WilkinsonAbstract:Debrisoquine is a major prototypic in-vivo probe used to assess polymorphic CYP2D6 activity in humans, based on the 0-8 h urinary excretion of unchanged drug and its 4-hydroxy metabolite (the so-called metabolic ratio). The primary purpose of the study was to investigate further the relationship between genotype and phenotype by determining the overall disposition characteristics of the drug in selected groups of healthy Swedish Caucasian individuals. Debrisoquine (20 mg) was orally administered to five poor metabolizers with no functional CYP2D6 gene, five heterozygous extensive metabolizers, five homozygous extensive metabolizers, five ultrarapid metabolizers with duplicated/triplicated CYP2D6*2 genes and one individual with 13 copies of CYP2D6*2. Peak plasma levels of Debrisoquine and 4-hydroxyDebrisoquine were attained within 2-4 h and then declined in a multi-exponential fashion over 96 h. However, the post 8-h period of the elimination process was characterized by irregular fluctuations that prevented formal pharmacokinetic analysis. Nevertheless, marked differences were apparent in the compounds' plasma level-time profiles between the CYP2D6 genotypes. For example, in the case of Debrisoquine, the mean ratio of the AUC(0-8) values was 22:22:7:6:1, corresponding to 0, 1, 2, 3/4 and 13 genes and, for 4-hydroxyDebrisoquine, the respective values were 1:7:19:28:17. The 0-96 h urinary recovery of Debrisoquine differed 100-fold between the genotypes, being essentially complete in poor metabolizers and zero in the individual with 13 CYP2D6*2 genes. 4-hydroxyDebrisoquine excretion increased according to the number of functional CYP2D6 genes. A highly significant correlation (r(s) = 0.95, P < 0.001) was observed between the plasma AUC(0-8) ratio for Debrisoquine to 4-hydroxyDebrisoquine and the 0-8 h urinary metabolic ratio. This study demonstrates that the number of functional CYP2D6 alleles is critically important in the plasma concentration-time curves of Debrisoquine and its CYP2D6-mediated 4-hydroxy metabolite. Concentration-related pharmacologic effects would be expected to be similarly affected by gene dosage and it is likely that the same situation also applies to other drugs whose elimination is importantly determined by this enzyme; for example, many antidepressants and neuroleptics, antiarrhythmic agents, beta-adrenoceptor antagonists and opiates.
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ten percent of north spanish individuals carry duplicated or triplicated cyp2d6 genes associated with ultrarapid metabolism of Debrisoquine
Pharmacogenetics, 1999Co-Authors: Maria Luisa Bernal, Marja-liisa Dahl, Inger Johansson, Magnus Ingelmansundberg, Blanca Sinues, Roman A Mclellan, Agneta Wennerholm, Leif BertilssonAbstract:Ten percent of North Spanish subjects carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of Debrisoquine.
Adrian Llerena - One of the best experts on this subject based on the ideXlab platform.
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cyp2d6 1584c g promoter polymorphism and Debrisoquine ultrarapid hydroxylation in healthy volunteers
Pharmacogenomics, 2013Co-Authors: Adrian Llerena, Pedro Dorado, Eva M Penaslledo, Idilio Gonzalez, Ronald Ramirez, Luis R Calzadilla, Mayra Alvarez, Maria Eg Naranjo, Barbaro PerezAbstract:Background & aim: The CYP2D6 -1584C>G polymorphism (rs1080985) has been identified as a major factor for CYP2D6 expression and function, with the mutant -1584G promoter type being consistently associated with significantly greater expression than -1584C. It may therefore be associated with ultrarapid metabolism. The objective of the present study was to explore the relationship between the CYP2D6 -1584C>G polymorphism and the Debrisoquine metabolic ratio in healthy volunteers in order to evaluate its potential impact on the ultrarapid CYP2D6 hydroxylation capacity. Materials & methods: The CYP2D6 -1584C>G polymorphism was analyzed in 320 unrelated healthy individuals who were previously phenotyped for Debrisoquine hydroxylation. Results: The metabolic ratio (log10 mean ± standard deviation) of individuals with the -1584G allele was lower than that of individuals with the -1584C allele for carriers of one active CYP2D6 gene (-0.13 ± 0.33 and 0.17 ± 0.52, respectively; p < 0.05) or two active CYP2D6 genes (...
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pharmacogenetics of Debrisoquine and its use as a marker for cyp2d6 hydroxylation capacity
Pharmacogenomics, 2009Co-Authors: Adrian Llerena, Pedro Dorado, Eva M PenaslledoAbstract:Debrisoquine hydroxylation polymorphism is by far the most thoroughly studied genetic polymorphism of the CYP2D6 drug-metabolizing enzyme. Debrisoquine hydroxylation phenotype has been the most used test in humans to evaluate CYP2D6 activity. Two Debrisoquine hydroxylation phenotypes have been described: poor and extensive metabolizers. A group with a very low Debrisoquine metabolic ratio within the extensive metabolizers, named ultrarapid metabolizers, has also been distinguished. This CYP2D6 variability can be for a large part alternatively determined by genotyping, which appears to be of clinical importance given CYP2D6 involvement in the metabolism of a large number of commonly prescribed drugs. CYP2D6 pharmacogenetics may then become a useful tool to predict drug-related side effects, interactions or therapeutic failures. However, a number of reasons appear to have made research into this field lag behind. The present review focuses on the relevance of genetics and environmental factors for determining Debrisoquine hydroxylation phenotype, as well as the relevance of CYP2D6 genetic polymorphism in psychiatric patients treated with antipsychotic drugs.
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determination of Debrisoquine and 4 hydroxyDebrisoquine by high performance liquid chromatography application to the evaluation of cyp2d6 genotype and Debrisoquine metabolic ratio relationship
Clinical Chemistry and Laboratory Medicine, 2005Co-Authors: Pedro Dorado, Adrian Llerena, J. Cobaleda, Roland Berecz, Macarena C Caceres, Idilio GonzalezAbstract:The drug-metabolizing cytochrome P450 (CYP) enzyme CYP2D6 is involved in the metabolism of several clinically important drugs. So far more than 50 different CYP2D6 allelic variants have been described, and thus there is an increased need for routine high-performance liquid chromatography (HPLC) methods for the evaluation of the functional implication of CYP2D6 polymorphism. Debrisoquine is metabolized to 4-hydroxyDebrisoquine by CYP2D6, and therefore it has been used widely to determine the hydroxylation capacity of the enzyme. The aim of the present study was to develop a simple, accurate HPLC method with ultraviolet detection for the measurement of Debrisoquine and 4-hydroxyDebrisoquine in urine for evaluation of the relationship between CYP2D6 enzyme activity and genotypes. For the HPLC determination, a C18 extraction column was used with a flow rate of 0.8 mL/min and detection at 210 nm. The compounds were eluted from the column in less than 10 min. Coefficients of variation at all concentrations were less than 4% for both compounds. The Debrisoquine/4-hydroxyDebrisoquine ratio (Debrisoquine metabolic ratio) was determined in a panel of 16 Caucasian healthy volunteers with zero (poor metabolizers), one, two or more than two (ultrarapid metabolizers) CYP2D6 active genes. Significant correlation (p<0.05) between the number of CYP2D6 active genes and the hydroxylation capacity of the enzyme was found. The present HPLC method was simple, fast and accurate, and thus will be useful for the evaluation of CYP2D6 hydroxylation capacity in pharmacogenetic studies.
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qtc interval lengthening is related to cyp2d6 hydroxylation capacity and plasma concentration of thioridazine in patients
Journal of Psychopharmacology, 2002Co-Authors: Adrian Llerena, Roland Berecz, Alfredo De La Rubia, Pedro DoradoAbstract:Thioridazine cardiotoxicity has been associated with a prolonged heart-rate corrected QT (QTc) interval. However, no systematic studies have been performed on patients at therapeutic doses. The present study aimed to evaluate the influence of dose and plasma concentration of thioridazine and CYP2D6 enzyme status on the QTc interval in psychiatric patients. Sixty-five Spanish European psychiatric patients receiving thioridazine antipsychotic monotherapy were studied. The plasma levels of thioridazine and its metabolites were determined by high-performance liquid chromatography. All patients were phenotyped for CYP2D6 activity with Debrisoquine during treatment. Thirty-five patients (54%) had a QTc interval over 420 ms. The lengthening of QTc interval was correlated with plasma concentration (p < 0.05) and daily dose (p < 0.05) of thioridazine. CYP2D6 enzyme hydroxylation capacity, evaluated by Debrisoquine metabolic ratio (MR) (p < 0.05) and thioridazine/mesoridazine ratio (p < 0.05), was also correlated with QTc intervals. The present study shows the relationship between QTc interval lengthening among psychiatric patients treated at therapeutical doses with the dose and the plasma concentration of thioridazine. Since Debrisoquine MR has been shown to be correlated with the QTc intervals, CYP2D6 enzyme hydroxylation capacity might be relevant in determining the risk for QTc interval lengthening. Patients with impaired CYP2D6 enzyme activity due to enzyme inhibition by thioridazine might be more prone to increased risk of sudden death due to torsade de pointes type cardiac dysrhythmia.
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effect of thioridazine dosage on the Debrisoquine hydroxylation phenotype in psychiatric patients with different cyp2d6 genotypes
Therapeutic Drug Monitoring, 2001Co-Authors: Adrian Llerena, Roland Berecz, Alfredo De La Rubia, Pedro M Fernandezsalguero, Pedro DoradoAbstract:Sixteen hospitalized white European Spanish psychiatric patients treated with thioridazine alone were studied with respect to CYP2D6 genotype, Debrisoquine metabolic ratio (MR), and the plasma levels of thioridazine and its metabolites mesoridazine and sulforidazine. After decreasing the dose of thioridazine the Debrisoquine MR and thioridazine plasma levels were redetermined. At the initial determination (regular clinical doses, 20-300 mg/day), 14 of 16 patients (88%) were classified as poor metabolizers of Debrisoquine (PMs). However, after complete withdrawal of thioridazine in 10 patients, all 10 became extensive metabolizers except two who were genotypically PMs (*4/*4). The inhibition of Debrisoquine metabolism was genotype dependent. All patients with wt/wt genotype treated with a dose 150 mg/d were phenotypically PMs, all patients with wt/*4 genotype treated with a dose of 50 mg/d or greater were PMs. The Debrisoquine MR from all dose changes correlated with the dose (p < 0.001) and plasma level (p < 0.001) of thioridazine. The CYP2D6 hydroxylation capacity was inhibited by thioridazine as determined by the Debrisoquine MR. This inhibition was reversible by thioridazine withdrawal, and thus seems to be dose dependent and related to CYP2D6 genotype. One must consider the effects of thioridazine dosage on CYP2D6, because it may influence the metabolism of concomitant drugs or produce clinically important adverse effects such as cardiotoxicity. An awareness of this problem and cautious dosage adjustment of other drugs metabolized by the same enzyme are recommended during treatment with thioridazine.
Magnus Ingelmansundberg - One of the best experts on this subject based on the ideXlab platform.
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a novel mutant variant of the cyp2d6 gene cyp2d617 common in a black african population association with diminished Debrisoquine hydroxylase activity
British Journal of Clinical Pharmacology, 2003Co-Authors: Collen Masimirembwa, Leif Bertilsson, Julia A Hasler, Irene Persson, Magnus IngelmansundbergAbstract:1. The Debrisoquine hydroxylase (CYP2D6) is polymorphically distributed. Not only are there differences in the proportions of extensive metabolisers to poor metabolisers in various ethnic groups, but there are also pronounced variations in the metabolic capacity among those classified as extensive metabolisers. 2. The mean Debrisoquine metabolic ratio of Caucasian extensive metabolisers is lower than that for a number of African populations. In the present study, we have searched for novel CYP2D6 mutations to explain the diminished enzyme activity in African populations. 3. Three Zimbabwean Shona subjects with EM phenotypes (metabolic ratios for Debrisoquine of 0.4, 1.5 and 10.5 respectively) were selected and the open reading frame of the CYP2D6 gene of each was sequenced. 4. The subject with metabolic ratio of 10.5 was found to be homozygous for an allele with a nucleotide exchange in exon 2, 1111C-->T causing a 107Thr-->Ile amino acid exchange in a conserved region of the enzyme. In addition, he was homozygous for the 2938C-->T and 4268G-->C mutations causing 296Arg-->Ser and 486Ser-->Thr amino acid substitution found in the CYP2D6*2 allele. 5. Seventy-six Zimbabwean Shona subjects were subsequently genotyped for the 1111C-->T mutation and for the intron 1 gene conversion present in the CYP2D6*2 gene. The 1111C-->T mutation was found at an allele frequency of 34% and was only present in alleles carrying the gene conversion in intron 1 indicative for the CYP2D6*2 gene. 6. This allele (CYP2D6*17), containing the 1111C-->T, 2938C-->T and 4268G-->C mutations, was found to be strongly associated with lower capacity for Debrisoquine hydroxylation. We therefore postulate that the CYP2D6*17 allele might contribute to the molecular basis of the previously established diminished Debrisoquine hydroxylase activity in African Bantu populations.
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decreased capacity for Debrisoquine metabolism among black tanzanians analyses of the cyp2d6 genotype and phenotype
Pharmacogenetics, 1999Co-Authors: Agneta Wennerholm, Marja-liisa Dahl, Leif Bertilsson, Inger Johansson, Magnus Ingelmansundberg, Christina Alm, Amos Y Massele, Mary Jande, Yakoub Adenabdi, Lars L GustafssonAbstract:The cytochrome P450 2D6 (CYP2D6) genotypes and phenotypes of 106 unrelated, healthy black Tanzanians of Bantu origin were investigated. The results revealed a population with a generally decreased capacity to metabolize the CYP2D6 substrate Debrisoquine with 59% of the Tanzanian extensive metabolise
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ten percent of north spanish individuals carry duplicated or triplicated cyp2d6 genes associated with ultrarapid metabolism of Debrisoquine
Pharmacogenetics, 1999Co-Authors: Maria Luisa Bernal, Marja-liisa Dahl, Inger Johansson, Magnus Ingelmansundberg, Blanca Sinues, Roman A Mclellan, Agneta Wennerholm, Leif BertilssonAbstract:Ten percent of North Spanish subjects carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of Debrisoquine.
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Debrisoquine and s mephenytoin hydroxylation phenotypes and genotypes in a korean population
Pharmacogenetics, 1996Co-Authors: Marja-liisa Dahl, Inger Johansson, Magnus Ingelmansundberg, Leif BertilssonAbstract:One hundred and fifty-two healthy Korean volunteers were phenotyped with Debrisoquine and mephenytoin and genotyped with respect to CYP2D6. The Debrisoquine metabolic ratio (MR) varied between 0.09 and 6.3, and all subjects were thus classified as extensive metabolizers of Debrisoquine. Polymerase c
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Debrisoquine and s mephenytoin hydroxylation phenotypes and genotypes in a korean population
Pharmacogenetics, 1996Co-Authors: Hyungkeun Roh, Marja-liisa Dahl, Inger Johansson, Magnus Ingelmansundberg, Youngnam Cha, Leif BertilssonAbstract:One hundred and fifty-two healthy Korean volunteers were phenotyped with Debrisoquine and mephenytoin and genotyped with respect to CYP2D6. The Debrisoquine metabolic ratio (MR) varied between 0.09 and 6.3, and all subjects were thus classified as extensive metabolizers of Debrisoquine. Polymerase chain reaction (PCR)-based amplification of genomic DNA with primers specific for the C188-->T mutation present in exon 1 of the CYP2D6*10B allele was performed and revealed an allele frequency of 0.51 in this Korean population. Forty-three subjects (28%) were homozygous for CYP2D6*10B, 69 subjects (45%) were heterozygous for this allele, while in 40 subjects (26%) no exon 1 mutation could be found. All subjects except one homozygous for the wild type allele had MRs below 0.75 whereas the MR was higher than 0.99 in all subjects homozygous for the CYP2D6*10B allele. The MRs in the three genotype groups were significantly different (p T mutation is the major cause of diminished CYP2D6 activity in Koreans. In this Korean population, the MR of Debrisoquine was shifted towards higher values (lower CYP2D6 activity) compared with Caucasian populations but the shift appeared to be less pronounced than earlier shown for Chinese. Twenty-four subjects (16%) were poor metabolizers of S-mephenytoin as indicated by the S/R mephenytoin ratio of about 1. Twenty-three of these were genotyped with respect to the defect CYP2C19-alleles CYP2C19*2 and CYP2C19*3. Of the 46 poor metabolizer alleles, 32 (70%) were CYP2C19*2 and the remaining 14 (30%) were CYP2C19*3. Thus, the defect CYP2C19*2 and CYP2C19*3-alleles explained 100% of the 23 Korean poor metabolizers of S-mephenytoin.
Inger Johansson - One of the best experts on this subject based on the ideXlab platform.
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decreased capacity for Debrisoquine metabolism among black tanzanians analyses of the cyp2d6 genotype and phenotype
Pharmacogenetics, 1999Co-Authors: Agneta Wennerholm, Marja-liisa Dahl, Leif Bertilsson, Inger Johansson, Magnus Ingelmansundberg, Christina Alm, Amos Y Massele, Mary Jande, Yakoub Adenabdi, Lars L GustafssonAbstract:The cytochrome P450 2D6 (CYP2D6) genotypes and phenotypes of 106 unrelated, healthy black Tanzanians of Bantu origin were investigated. The results revealed a population with a generally decreased capacity to metabolize the CYP2D6 substrate Debrisoquine with 59% of the Tanzanian extensive metabolise
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ten percent of north spanish individuals carry duplicated or triplicated cyp2d6 genes associated with ultrarapid metabolism of Debrisoquine
Pharmacogenetics, 1999Co-Authors: Maria Luisa Bernal, Marja-liisa Dahl, Inger Johansson, Magnus Ingelmansundberg, Blanca Sinues, Roman A Mclellan, Agneta Wennerholm, Leif BertilssonAbstract:Ten percent of North Spanish subjects carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of Debrisoquine.
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Debrisoquine and s mephenytoin hydroxylation phenotypes and genotypes in a korean population
Pharmacogenetics, 1996Co-Authors: Marja-liisa Dahl, Inger Johansson, Magnus Ingelmansundberg, Leif BertilssonAbstract:One hundred and fifty-two healthy Korean volunteers were phenotyped with Debrisoquine and mephenytoin and genotyped with respect to CYP2D6. The Debrisoquine metabolic ratio (MR) varied between 0.09 and 6.3, and all subjects were thus classified as extensive metabolizers of Debrisoquine. Polymerase c
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Debrisoquine and s mephenytoin hydroxylation phenotypes and genotypes in a korean population
Pharmacogenetics, 1996Co-Authors: Hyungkeun Roh, Marja-liisa Dahl, Inger Johansson, Magnus Ingelmansundberg, Youngnam Cha, Leif BertilssonAbstract:One hundred and fifty-two healthy Korean volunteers were phenotyped with Debrisoquine and mephenytoin and genotyped with respect to CYP2D6. The Debrisoquine metabolic ratio (MR) varied between 0.09 and 6.3, and all subjects were thus classified as extensive metabolizers of Debrisoquine. Polymerase chain reaction (PCR)-based amplification of genomic DNA with primers specific for the C188-->T mutation present in exon 1 of the CYP2D6*10B allele was performed and revealed an allele frequency of 0.51 in this Korean population. Forty-three subjects (28%) were homozygous for CYP2D6*10B, 69 subjects (45%) were heterozygous for this allele, while in 40 subjects (26%) no exon 1 mutation could be found. All subjects except one homozygous for the wild type allele had MRs below 0.75 whereas the MR was higher than 0.99 in all subjects homozygous for the CYP2D6*10B allele. The MRs in the three genotype groups were significantly different (p T mutation is the major cause of diminished CYP2D6 activity in Koreans. In this Korean population, the MR of Debrisoquine was shifted towards higher values (lower CYP2D6 activity) compared with Caucasian populations but the shift appeared to be less pronounced than earlier shown for Chinese. Twenty-four subjects (16%) were poor metabolizers of S-mephenytoin as indicated by the S/R mephenytoin ratio of about 1. Twenty-three of these were genotyped with respect to the defect CYP2C19-alleles CYP2C19*2 and CYP2C19*3. Of the 46 poor metabolizer alleles, 32 (70%) were CYP2C19*2 and the remaining 14 (30%) were CYP2C19*3. Thus, the defect CYP2C19*2 and CYP2C19*3-alleles explained 100% of the 23 Korean poor metabolizers of S-mephenytoin.
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phenotype and genotype analysis of Debrisoquine hydroxylase cyp2d6 in a black zimbabwean population reduced enzyme activity and evaluation of metabolic correlation of cyp2d6 probe drugs
European Journal of Clinical Pharmacology, 1996Co-Authors: Collen Masimirembwa, Inger Johansson, Julia A Hasler, L Bertilssons, O Ekberg, Magnus IngelmansundbergAbstract:Objective: Debrisoquine hydroxylase (CYP2D6) is responsible for the oxidative metabolism of many clinically used drugs. Since this enzyme has been poorly studied in the southern part of Africa, we examined the CYP2D6 phenotypes and genotypes in 103 unrelated black Zimbabweans. Methods: Phenotyping for CYP2D6 activity was done using Debrisoquine and metoprolol as probe drugs by measuring the urinary metabolic ratio (MR) of parent drug to metabolite concentration ratios. Genotyping was done using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), single-strand conformation polymorphism (SSCP) and sequencing analyses with respect to CYP2D6 variants of interest. Results and conclusion: Phenotyping with Debrisoquine revealed two poor metabolisers (PMs), whereas 5 subjects out of 94 were PMs using metoprolol as probe drug. Genotypes predictive of the poor metaboliser status were observed for the two subjects who were PMs with both probe drugs, whereas no mutations could explain the PM phenotype for metoprolol among the three remaining subjects, a fact possibly explained by lack of compliance in metoprolol intake. There was a moderate correlation of 0.67 between the Debrisoquine and metoprolol metabolic ratios in the 89 subjects who were extensive metabolisers for both probe drugs. The median values for the metabolic ratios for Debrisoquine and metoprolol as probe drugs were 1.00 and 1.35, respectively, which are higher than those observed in Caucasian populations. This is indicative of a decreased capacity for metabolism of CYP2D6 substrates by Zimbabweans compared to Caucasians. Evaluation of the DNA samples for the known allelic variants CYP2D6A, CYP2D6B, CYP2D6C,CYP2D6D or CYP2D6Ch 1 yielded no explanation for these results.
