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Biomedical subjects

L Bertilsson

Publications and source records attributed to L Bertilsson.

At least 73 records · Page 4Linked to original sources
PubMed1997

Significance of monitoring plasma levels of amitriptyline, and its hydroxylated and desmethylated metabolites in prediction of the clinical outcome of depressive state.

The clinical significance of monitoring the plasma levels of amitriptyline and its metabolites in prediction of the clinical outcome of depressive episode was investigated in 49 inpatients. Discriminant analysis of drug concentrations (at two weeks after initiation of drug treatment) and clinical outcome revealed that increasing the plasma levels of amitriptyline, cis-isomers of hydroxylated metabolites (Z-10-hydroxyamitriptyline and Z-10-hydroxynortriptyline) predicted a better clinical outcome, while increasing of plasma levels of nortriptyline and trans-isomers of hydroxylated metabolites (E-10-hydroxyamitriptyline and E-10-hydroxynortriptyline) were shown to predict a poor clinical outcome in the depressive episode of the subjects, and that clinical outcome of approximately 73% of the subjects could be correctly predicted.

Adult↗
PubMed1997

Pharmacogenetics of antidepressants: clinical aspects.

Plasma concentrations and response to antidepressants vary considerably between patients treated with similar dosages. Most antidepressants and also antipsychotics are metabolized by the polymorphic debrisoquine/sparteine hydroxylase, i.e., cytochrome P450 (CYP)2D6. About 7% of Caucasians are poor metabolizers (PM), and such patients might develop adverse drug reactions when treated with recommended doses of, for example, tricyclic antidepressants. In contrast, ultrarapid metabolizers with multiple CYP2D6 genes might require high doses of such drugs for optimal therapy. The mean CYP2D6 activity is lower in Oriental than in Caucasian populations, because of a frequent mutation causing decreased enzyme activity. Drugs metabolized by the same enzyme may interact with each other. For example, the potent CYP2D6 inhibitor fluoxetine increases the plasma concentrations of tricyclic antidepressants. Another enzyme catalyzing the metabolism of antidepressants is the polymorphic S-mephenytoin hydroxylase. CYP2C19, which catalyses the metabolism of, for example, citalopram, clomipramine and moclobemide. Various probe drugs may be used for phenotyping CYP2D6 (debrisoquine, dextromethorphan and sparteine) and CYP2C19 (mephenytoin and omeprazole). Allele-specific polymerase chain reaction (PCR)-based methods are now available for genotyping using leukocyte DNA. A major advantage of genotyping compared with phenotyping is that the former may be performed in blood samples from patients irrespective of treatment.

Adult↗
PubMed1996

Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype.

The relationship between the CYP2D6 genotype and the steady state plasma levels of nortriptyline (NT), its main active metabolite 10-hydroxynortriptyline (10-OH-NT) and the NT/10-OH-NT ratio were studied in 21 Caucasian depressed patients treated with 100-150 mg NT daily. The patients had participated in a previously published study investigating the role of NT and 10-OH-NT for the therapeutic effect of NT, and the plasma level data were from that study. In the present follow-up study, the patients were genotyped with respect to the polymorphic CYP2D6 by allele-specific PCR amplification and EcoRI RFLP. One poor metabolizer (PM) was identified and she had the highest plasma concentration of NT. Among the 20 extensive metabolizers (EM), the genotype (homozygous versus heterozygous EM) alone was not found to explain the variance in dose-corrected NT concentrations, but contributed significantly when gender was also taken into account. Together, these factors accounted for 59% of the variability in NT levels. Female patients had higher plasma levels of NT than male patients. 10-OH-NT levels were influenced by genotype, and NT/10-OH-NT ratio by genotype and gender. The present follow-up study confirms a relationship between the CYP2D6 genotype and the plasma levels of NT and its active metabolite. Identification of PM by genotyping should be of value for the prediction of the plasma levels and, consequently, the lower than average dose of NT required for optimal therapy. Also among EM, the genotype contributes to the variability in NT and 10-OH-NT levels but alone is of limited practical value for the prediction of optimal dosage.

Adult↗
PubMed1996

The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol.

BACKGROUND: Most antidepressant and neuroleptic agents are metabolized by the polymorphic cytochrome P450 enzyme CYP2D6. This study evaluates the importance of the CYP2D6 genotype for the disposition of the neuroleptic agents perphenazine and zuclopenthixol. METHODS: Patients treated with neuroleptic agents (n = 36) were studied prospectively with regard to CYP2D6 genotype and neuroleptic plasma concentration during oral treatment. Because no patient provided enough samples for individual kinetic modeling, a bayesian approach was used for determination of the clearance. Population kinetic parameters for this procedure were collected from retrospective therapeutic drug monitoring data (n = 113) by use of a nonparametric approach. RESULTS: The CYP2D6 genotype significantly predicted the oral clearance of perphenazine and zuclopenthixol (p < 0.01 by multiple regression). The difference in clearance between homozygous extensive metabolizers and poor metabolizers was threefold for perphenazine and twofold for zuclopenthixol. CONCLUSION: The results show that the genotype for CYP2D6 is closely related to the oral clearances of perphenazine and zuclopenthixol. If this finding can be confirmed in a larger population, genotyping may become an important tool for the dosing of these two neuroleptic agents.

Administration, Oral↗
PubMed1996

Disposition of fluvoxamine in humans is determined by the polymorphic CYP2D6 and also by the CYP1A2 activity.

BACKGROUND: Fluvoxamine is a selective serotonin reuptake inhibitor used widely in the treatment of depression and other psychiatric diseases, but little is known about the specific isozymes involved in its metabolism. This study investigated the relationship between fluvoxamine disposition and the polymorphic CYP2D6 and the polycyclic aromatic hydrocarbon (as contained in cigarette smoke) inducible CYP1A2. METHODS: Fluvoxamine (50 mg orally) was given to 10 extensive metabolizers and four poor metabolizers of debrisoquin, and concentrations were assessed in plasma by high performance liquid chromatography. Five of the extensive metabolizers and one of the poor metabolizers were smokers of more than 10 cigarettes per day. The CYP1A2 activity was determined by means of a urinary caffeine test. RESULTS: Compared with nonsmoking extensive metabolizers, nonsmoking poor metabolizers had a statistically significant (p = 0.02, Mann-Whitney U test) about twofold higher maximum plasma concentration, longer half-life, and fivefold lower oral clearance of fluvoxamine. The oral clearance of fluvoxamine correlated to the CYP1A2 index in the 14 subjects (rs = 0.58; p < 0.05; Spearman rank correlation). CONCLUSION: The disposition of fluvoxamine in humans is associated with the polymorphic CYP2D6 activity, but CYP1A2 also seems to be involved.

Adrenergic Agents↗
PubMed1996

Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans.

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.

Adult↗
PubMed1996

A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black African population: association with diminished debrisoquine hydroxylase activity.

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.

Black People↗
PubMed1996

Debrisoquine and S-mephenytoin hydroxylation phenotypes and genotypes in a Korean population.

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 < 0.0001; Kruskal-Wallis test). Eco RI RFLP analysis of DNA from six subjects with debrisoquine MRs < or = 0.11 revealed that only one (MR 0.09) carried a duplicated CYP2D6*Z-gene (CYP2D6*2X2) as indicated by the Eco RI 12.1 kb haplotype. It is concluded that, as shown earlier for Chinese and Japanese populations, the CYP2D6*10B-allele containing the C188-->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.

Adult↗
PubMed1996

S-mephenytoin hydroxylation phenotype and CYP2C19 genotype among Ethiopians.

The polymorphic metabolism of S-mephenytoin and the distribution of two known deleterious mutant CYP2C19 alleles was determined among 114 healthy unrelated black Ethiopians. Six subjects (5.2%) were poor metabolizers (PMs) of S-mephenytoin. The frequencies of the defective CYP2C19*2 (CYP2C19m1) and CYP2C19*3 (CYP2C19m2) alleles were 0.14 and 0.02, respectively. Three of the PMs were homozygous for the CYP2C19*2 allele and the remaining three PMs were heterozygous for both the CYP2C19*2 and CYP2C19*3 mutant alleles. It is concluded that the frequency of PMs for S-mephenytoin is similar in Ethiopians, Zimbabweans and Caucasians and that the CYP2C19*3 allele, for the first time identified in a black population, together with the CYP2C19*2 allele account for all of the defective CYP2C19 alleles among the Ethiopian PMs.

Alleles↗
PubMed1996

CYP2C19 genotype and phenotype determined by omeprazole in a Korean population.

Omeprazole (20 mg orally) was given to 103 healthy Korean subjects and blood was taken 3 h after administration. The plasma concentration ratio of omeprazole and hydroxyomeprazole, used as an index of CYP2C19 activity, was bimodally distributed. Thirteen subjects (12.6%) were identified as poor metabolizers (PMs) with an omeprazole hydroxylation ratio of 6.95 or higher. Among the 206 CYP2C19 alleles, CYP2C19*2 and CYP2C19*3 were found in 43 alleles (21%) and 24 alleles (12%), respectively. Twelve subjects (12%) carried two defect alleles (*2/*2, *2/*3 or *3/*3), 43 subjects (42%) were heterozygous for a mutated (*2 or *3) and a wild type (*1) allele, and the remaining 48 subjects (47%) were homozygous for the wild type allele. The distributions of the metabolic ratio between these three genotype groups were significantly different (Kruskal-Wallis test: p < 0.0001). The genotypes of 19 additional Korean PMs has been identified in a previous mephenytoin study. From a total of 32 PMs, 31 were genotypically PMs by analysis of the CYP2C19*2 and *3 alleles and only one PM subject was found to be heterozygous for the *1 and *2 alleles. At present it cannot be judged whether this subject has a defective allele with a so-far unidentified mutation or a true wild type allele. We thus confirm a high incidence (12.6%) of PMs of omeprazole in Koreans and of the 32 Korean PMs 97% could be identified by the genotype analysis.

Administration, Oral↗
PubMed1996

Antidepressants and drug-metabolizing enzymes--expert group report.

Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.

Antidepressive Agents↗
PubMed1996

Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles.

The debrisoquine hydroxylase (CYP2D6) catalyzes the oxidative metabolism of more than 40 different clinically important drugs. The CYP2D6 gene is highly polymorphic. Defect alleles, causing the poor metabolizer phenotype, and also alleles with duplicated or multiduplicated active genes, causing ultrarapid metabolism, have been described. In the current investigation, we have evaluated the CYP2D6 phenotype (n = 115) and genotype (n = 122) among healthy Ethiopians. Only two subjects (1.8%) exhibited metabolic reaction (MR) for debrisoquine > 12.6 and were classified as poor metabolizers. A mutation in exon 1 causing a 34Pro --> Ser amino acid exchange, typical of the Chinese CYP2D6*10B (Ch1) allele and yielding an unstable enzyme, was present among 16% of the population and the carriers exhibited a high MR (0.9-5.0). Increased MR was also found among 18% of the subjects with a 107Thr --> Ile mutation associated to the CYP2D6*17(Z) allele causing diminished activity of CYP2D6 in vivo. Interestingly, 29% of the population investigated carried alleles with duplicated or multiduplicated CYP2D6 genes, indicative of ultrarapid metabolism. Xbal and EcoRI RFLP analyses identified individuals having new alleles with four or five CYP2D6*2(L) genes. Subjects with duplicated or multiduplicated CYP2D6*2 genes exhibited the lowest MR. These results suggest that the Ethiopian population, in comparison to Caucasian, Oriental and other Black populations, is genetically different with respect to the constitution of the CYP2D locus. The results also show that subjects carrying duplicated or multiduplicated active CYP2D6 genes are very common in certain ethnic groups, implicating this issue of potential global importance.

Alleles↗
PubMed1995

Phenotyping and genotyping of S-mephenytoin hydroxylase (cytochrome P450 2C19) in a Shona population of Zimbabwe.

The S-mephenytoin hydroxylase has recently been identified as cytochrome P450 2C19 (CYP2C19). This enzyme metabolizes mephenytoin, diazepam, omeprazole, and citalopram and has been shown to be polymorphically distributed. One clinical implication of CYP2C19-dependent drug metabolism for persons who reside in tropical regions is in the use of the antimalarial drug chloroguanide hydrochloride, which is apparently biotransformed to its active metabolite by this isozyme. In this investigation we studied mephenytoin metabolism in 103 black Zimbabwean Shona subjects. Four were identified as poor metabolizers (4%). This prevalence is comparable to that in white subjects (2% to 5%) but lower than the 15% to 20% incidence of poor metabolizers among Oriental subjects. Of the subjects phenotyped, 84 were genotyped for the G-->A mutation in exon 5 of CYP2C19, which creates a cryptic splice site, causing the production of a nonfunctional protein. Three of the four poor metabolizers were homozygous for this mutation, whereas the fourth one was heterozygous. The G-->A mutation has been shown to predict the incidence more than 60% of poor metabolizers among white subjects and Japanese subjects, and in the current investigation we also obtained a similar relationship in the black population.

Adult↗
PubMed1995

Enantioselective determination of mianserin and its desmethyl metabolite in plasma during treatment of depressed Japanese patients.

A method for the analysis of the enantiomers of mianserin and its main metabolite desmethylmianserin in plasma using a chiral AGP high performance liquid chromatography column is described. In the majority of 66 depressed Japanese patients, the concentration of the more active S(+)-mianserin was higher than that of the R(-)-enantiomer. The mean S/R ratio was 1.9 +/- 0.9 (SD) (range 0.5-4.8). The concentration of S(+)-varied between 19 and 223 nM, while that of the R(-)-mianserin varied between 14 and 72 nM. Among 42 of the 66 plasma samples in which the enantiomers of desmethylmianserin could be measured, the R-form predominated in all but one. S-Desmethylmianserin was in most of the samples present in concentrations of < 10 nM (limit of detection). Analysis of the enantiomers of mianserin and desmethylmianserin might allow the establishment of a closer relationship between plasma levels and clinical effects.

Adult↗
PubMed1995

Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects.

The CYP2D6 genotype and the debrisoquine and mephenytoin hydroxylation phenotypes were studied in 63 Oriental subjects including 21 Chinese, 21 Japanese and 21 Koreans. All subjects were extensive metabolizers of debrisoquine. The incidence of the S-mephenytoin poor metabolizer phenotype was 14% in the Chinese, 24% in the Japanese and 24% in the Korean population, respectively, which is similar to previous reports. The CYP2D6 genotype was analysed by Xba I and Eco RI RFLP, and by allele-specific PCR analysis for the presence of several allelic variants of the CYP2D locus. No CYP2D6A or CYP2D6B alleles, two of the most common defect alleles among Caucasians, were found among the Oriental subjects. The frequency of the CYP2D6D allele was similar to that in Caucasian populations and consistent with the low incidence of the poor metabolizer phenotype in all three Oriental populations. The CYP2D6L2-allele with duplication of an active CYP2D6L gene was identified in one Korean and one Chinese allele in association with high CYP2D6 activity. The CYP2D6Ch alleles CYP2D6Ch1 and Ch2, identified by RFLP and PCR for the -1338C-->T and 188C-->T mutations, were the most frequent allelic variants in all three populations studied, and were related to a decreased CYP2D6 activity as previously shown in Chinese. In conclusion, the present pilot study revealed major similarities in the polymorphic CYP2D locus between Korean, Japanese and Chinese populations.

Adult↗
PubMed1995

Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype.

A single oral dose of omeprazole (20 mg) was given orally to 160 healthy Caucasian Swedish subjects and tested as a probe for CYP2C19. The study was nonrandomized and included seven subjects previously classified as poor metabolizers (PM) of S-mephenytoin. The ratio between the plasma concentrations of omeprazole and hydroxyomeprazole (metabolic ratio; MR) was determined by HPLC in a blood sample drawn 3 h after drug intake. In 17 subjects the test was repeated and the MRs of omeprazole on the two occasions were correlated (rs = 0.85; p < 0.0001). There was a significant correlation between the MR of omeprazole and the S/R mephenytoin ratio among 141 subjects, in whom both ratios were determined (rs = 0.63, p < 0.001). All seven PMs of S-mephenytoin had higher MRs of omeprazole (7.1-23.8) than extensive metabolizers (EM) (0.1-4.9). All 160 subjects and another 15 Caucasian Swedish PMs previously phenotyped with mephenytoin were analysed with respect to the presence of the CYP2C19m1 allele by PCR amplification of the intron 4/exon 5 junction followed by Sma I digestion. EMs heterozygous for the CYP2C19m1 gene had MRs of omeprazole and S/R ratios of mephenytoin that were higher than those of subjects who were homozygous for the wild-type allele (p = 0.0001). Nineteen of the 22 PMs were homozygous for the CYP2C19m1 gene. Three were heterozygous for this allele. Thus, 41 of the 44 alleles (93%) of PMs were defective CYP2C19m1. One of the remaining three PM alleles was subsequently found to contain the CYP2C19m2 mutation, which has earlier been shown to be associated with the PM phenotype in Oriental populations. In conclusion, the phenotype determined by omeprazole correlated with that of mephenytoin, and was in good agreement with the genotype.

2-Pyridinylmethylsulfinylbenzimidazoles↗