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Biomedical subjects

M L Dahl

Publications and source records attributed to M L Dahl.

At least 19 recordsLinked to original sources
PubMed1995

A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolizers of debrisoquin and risperidone.

The hydroxylation of the new antipsychotic drug risperidone to its main, active metabolite 9-hydroxyrisperidone is catalyzed by the hepatic cytochrome P450 enzyme CYP2D6, and cosegregates with the polymorphic hydroxylation of debrisoquin. We have previously examined central D2 dopamine and 5-HT2 receptor occupancy after 1 mg risperidone orally in three healthy subjects who were extensive metabolizers (EM) of debrisoquin, using positron emission tomography and the radioligands [11C]raclopride and [11C]NMSP. In this study, the same experimental design was repeated in two healthy poor metabolizers (PM) of debrisoquin to compare the D2 and 5-HT2 receptor occupancy induced by risperidone in EM and PM. The two PM had much higher plasma concentrations and longer elimination half-lives of risperidone than the three EM. Plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone partly overlapped among the EM and PM. D2 receptor occupancy was 50% and 54% in the two PM, as compared to 40%, 43% and 55% in the EM. 5-HT2 receptor occupancy was 63% and 73%, as compared to 45%, 56% and 68% in the EM. These findings support the view that the active 9-hydroxyl metabolite of risperidone contributes to the in vivo effects of risperidone in humans, and thus partly counterbalances the marked variability in the disposition of risperidone.

Adult↗
PubMed1995

Polymorphic drug metabolism in schizophrenic patients with tardive dyskinesia.

The metabolism of many neuroleptics cosegregates catalyzed by the polymorphic cytochrome P450 CYP2D6. The population can be phenotyped into extensive metabolizers (EM) and poor metabolizers (PM) with respect to this enzyme's activity. PM are likely to achieve higher than average concentrations of neuroleptic drugs in plasma, with an increased risk of extrapyramidal side effects, possibly including tardive dyskinesia. Sixteen white schizophrenic patients who had developed tardive dyskinesia during long-term neuroleptic treatment were phenotyped with debrisoquine and genotyped by CYP2D6-specific DNA amplification and EcoRI restriction fragment length polymorphism analysis. Only 1 (6%) of the 16 patients had a PM genotype, 8 (50%) were homozygous, and 7 (44%) were heterozygous EM. None had a CYP2D6 genotype indicative of ultrarapid debrisoquine hydroxylation capacity. The patients were also phenotyped with mephenytoin, a probe drug for another polymorphic cytochrome P450, CYP2C19. One patient was a PM of S-mephenytoin, which corresponds to the frequency found in healthy white volunteers. In conclusion, there was no overrepresentation of PM of debrisoquine or of S-mephenytoin among the 16 patients with neuroleptic-induced tardive dyskinesia. However, the PM of debrisoquine had the highest score on the Simpson-Angus Rating Scale and the second highest on the Abnormal Involuntary Movement Scale, despite a very low neuroleptic dose. Also, the debrisoquine MR correlated significantly with the SARS score (rs = 0.685, p < 0.05, N = 10), indicating a relationship between the degree of impaired CYP2D5 activity and the severity of extrapyramidal side effects during neuroleptic treatment.

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

Interphenotype differences in disposition and effect on gastrin levels of omeprazole--suitability of omeprazole as a probe for CYP2C19.

1. Fourteen healthy Swedish Caucasian subjects were given 20 mg of omeprazole orally each morning for 8 days. The subjects included five poor metabolisers (PM) of S-mephenytoin, four heterozygous extensive metabolisers (hetEM) and five subjects with a very rapid metabolism (rapidEM). 2. After the first dose, the relative mean areas under the plasma concentration vs time curve (AUC) of omeprazole in rapidEM, hetEM and PM were 1:3.7:20 (all different, P < 0.001). A similar relation was seen in the AUC(0,10 h) of the sulphone metabolite (1:3:12). Concentrations of hydroxyomeprazole were higher in EM than in PM confirming that the hydroxy, but not the sulphone metabolite, is formed by the S-mephenytoin hydroxylase (CYP2C19). After 8 days of treatment, the differences between groups were similar. 3. After both the first and the eighth doses, the omeprazole/hydroxyomeprazole plasma concentration ratio, determined 3 h after drug intake, correlated with the mephenytoin S/R ratio (rs = 0.94; P < 0.001; n = 14) suggesting that omeprazole might be used to phenotype for CYP2C19. 4. After the first dose of omeprazole, there was no difference in the AUC(0,10 h) of plasma gastrin between the three groups. From the first to the eighth dose, the AUC(0,10) of gastrin increased significantly in both hetEM and PM, while there was no change in the rapidEM. After the eighth dose, the AUC(0,10) of gastrin correlated significantly with the AUC of omeprazole in plasma (rs = 0.79; P < 0.01; n = 13).

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate.

OBJECTIVE: The aim of this study was to examine the relationships among clinical effects, central D2 dopamine receptor occupancy, and plasma concentrations of haloperidol in eight clinically stabilized schizophrenic outpatients who were responding to treatment with low doses of haloperidol decanoate. METHOD: During a 4-week interval of haloperidol decanoate dosage (dose range = 30-50 mg), the patients' D2 receptor occupancy was determined with positron emission tomography on two occasions. Plasma concentrations of haloperidol were determined with a sensitive high-performance liquid chromatography method. RESULTS: One week after injection of haloperidol decanoate, the mean D2 receptor occupancy was 73% (range = 60%-82%), and the mean plasma concentration of haloperidol was 4.6 nmol/liter (range = 2.9-9.7). After 4 weeks, the mean D2 receptor occupancy had decreased to 52% (range = 20%-74%), and the mean haloperidol concentration to 2.3 nmol/liter (range = 1.0-4.4). CONCLUSIONS: The D2 receptor occupancy 1 week after injection was high and comparable to that previously found in patients responding to acute treatment with classic neuroleptics. Prevention of relapse was maintained despite low D2 receptor occupancy during the latter part of the treatment interval. These observations indicate that continuously high D2 receptor occupancy may not be necessary to prevent schizophrenic relapses. The results emphasize the need for systematic clinical evaluation of intermittent low-dose treatment strategies.

Adult↗
PubMed1995

Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis.

Hydroxylation of debrisoquine, catalyzed by the cytochrome P450 CYP2D6 exhibits genetic polymorphism, with large inter-individual differences in metabolic capacity. About 7% of Caucasians carry deficient CYP2D6 alleles and lack the CYP2D6 enzyme (poor metabolizers). We have shown in two Swedish families, individuals carrying duplicated or amplified functional CYP2D6L-genes (CYP2D6L2), causing the opposite phenomenon, ultrarapid metabolism of debrisoquine. In the present study, the occurrence of extra copies of CYP2D6L-alleles was studied in relation to debrisoquine metabolic ratio (MR) in 270 Swedish Caucasians including 64 selected subjects with very rapid metabolism (MR < or = 0.2). Thirteen of the 64 subjects carried a duplicated CYP2D6-gene as identified by EcoRI and XbaI restriction fragment length polymorphism and allele-specific polymerase chain reaction-amplification of genomic DNA. A new allele with three active CYP2D6L-genes was identified, characterized by an XbaI 54 kilobase fragment. This indicates a preference of the CYP2D6L-gene to be amplified compared to other CYP2D6 genes. Only one subject with an MR higher than 0.2 carried the duplicated CYP2D6L-allele, also being heterozygous for the defect CYP2D6B-allele. The overall frequency of the duplicated/amplified CYP2D6-allele was about 1%, and was present in 40% of subjects with MRs < or = 0.1. Thus, other variant CYP2D6-genes may exist that cause increased CYP2D6 activity. In conclusion, a haplotype with duplicated or amplified functional CYP2D6 genes predicts, with high accuracy, ultrarapid metabolism of debrisoquine. Genotyping for this CYP2D locus variant might be of value in patients not responding to generally recommended doses of CYP2D6 substrates, to distinguish between high metabolic capacity and noncompliance.

Cytochrome P-450 CYP2D6↗
PubMed1994

Genetic polymorphism of cytochrome P450. Functional consequences and possible relationship to disease and alcohol toxicity.

The hepatic cytochrome P450 system participates in the oxidative metabolism of numerous endogenous and exogenous compounds. In total several hundred different P450s have been cloned, but it appears that in humans only about 5-10 isoforms account for the major part of drug metabolism. Some of these are polymorphically distributed in the population. Cytochrome P450 2D6 catalyzes the oxidation of over 25 clinically important drugs, eg neuroleptics, antidepressants and lipophilic beta-blockers. Seven % of Caucasians and 1% of Orientals are defective in this enzyme and clearance of drugs metabolized by the enzyme may be substantially decreased in these individuals, with potentially increased risks for side effects caused by the drug treatment. Some individuals are ultrarapid metabolizers and do not achieve therapeutic drug levels at ordinary doses. The molecular genetic basis of these polymorphisms are presented. Methods for genotyping, which can be of predictive value for a more efficient drug therapy, are discussed. Ethanol-inducible cytochrome P450 2E1 (CYP2E1) oxidizes ethanol and acetaldehyde, in addition to over 80 toxicologically important xenobiotics. Furthermore, this isozyme produces reactive oxy radicals which are implicated in the aetiology of alcoholic liver disease. The gene is polymorphic and a mutation in a putative binding site for HNF1, described to affect gene expression, is more rare among subjects with lung cancer as compared to healthy controls. Further studies might give an answer as to whether any of the polymorphic CYP2E1 alleles is associated with the sensitivity to obtain alcoholic liver disease.

Animals↗
PubMed1994

Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism.

The pharmacokinetics of mianserin and its main metabolite desmethylmianserin were studied in poor and extensive metabolizers of debrisoquin and of S-mephenytoin after a single oral dose of racemic mianserin. The debrisoquin metabolic ratio (MR) correlated significantly with area under the serum concentration-time curves (AUC) for (+/-)-mianserin and (+/-)-desmethylmianserin. Enantioselective high-performance liquid chromatographic analysis of mianserin showed that debrisoquin MR was related to AUC(0-12) for S(+)-mianserin (rs = 0.87; p = 0.001; n = 15) but not for R(-)-mianserin. The ratio between the AUC(0-12) for S(+)-mianserin and that for R(-)-mianserin was higher in poor metabolizers than in extensive metabolizers. Two extremely rapid extensive metabolizer subjects had the lowest mianserin S/R ratios. No differences in the pharmacokinetics of mianserin or desmethylmianserin were found between extensive metabolizers and poor metabolizers of S-mephenytoin. The study shows that the elimination of both mianserin and its main metabolite desmethylmianserin is dependent on CYP2D6 activity. Furthermore, the CYP2D6-dependent elimination of mianserin shows marked enantioselectivity for the more active S(+)-enantiomer of mianserin.

Administration, Oral↗
PubMed1994

Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms.

A large interindividual variability has previously been demonstrated in the bioavailability, steady-state plasma concentrations and clearance of clozapine, an atypical neuroleptic drug. To evaluate the importance of genetic factors in the metabolism of clozapine, its disposition after a single oral dose of 10 mg was studied in 15 healthy Caucasian volunteers. Five of the subjects were poor metabolisers (PM) of debrisoquine, five were PM of S-mephenytoin, and the remaining five were extensive metabolisers (EM) of both probe drugs. There was a 10-fold interindividual variation in Cmax and a 14-fold variation in AUC(0, 24) of clozapine among the 15 subjects studied. The mean (s.d.) Cmax was 117 (81) nmol l-1 and the mean AUC(0,24) value was 890 (711) nmol l-1 h. The value of t1/2,z varied 3-fold with a mean (s.d.) of 13.3 (5.0) h. There were no significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between PM and EM of debrisoquine, or between the two S-mephenytoin hydroxylation phenotypes. We conclude that neither of the major genetic polymorphisms of oxidative drug metabolism contribute to the large interindividual variability in clozapine pharmacokinetics.

Administration, Oral↗
PubMed1994

Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test.

In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S-mephenytoin hydroxylation polymorphism. The same 14 healthy subjects studied in that investigation were given 150 mg of caffeine. The reciprocal of plasma clozapine AUC (0,24), was correlated with an index of the N3-demethylation of caffeine (rs = 0.84; P = 0.0024), used as a measure of cytochrome P4501A2 (CYP1A2) activity. N1- and N7-demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (rs = 0.89 and 0.85; P = 0.0013 and 0.0023; respectively). No significant relationships with xanthine oxidase and N-acetyl transferase activity, also assessed by a caffeine test, were found. This study suggests that clozapine is metabolised by CYP1A2 to a major extent.

Administration, Oral↗
PubMed1993

Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine.

Deficient hydroxylation of debrisoquine is an autosomal recessive trait that affects approximately 7% of the Caucasian population. These individuals (poor metabolizers) carry deficient CYP2D6 gene variants and have an impaired metabolism of severely commonly used drugs. The opposite phenomenon also exists, and certain individuals metabolize the drugs very rapidly, resulting in subtherapeutic plasma concentrations at normal doses. In the present study, we have investigated the molecular genetic basis for ultrarapid metabolism of debrisoquine. Restriction fragment length polymorphism analysis of the CYP2D locus in two families with very rapid metabolism of debrisoquine [metabolic ratio (MR) for debrisoquine = 0.01-0.1] revealed the variant CYP2D6 gene CYP2D6L. Eco RI RFLP and Xba I pulsed-field gel electrophoresis analyses showed that this gene had been amplified 12-fold in three members (father and his two children) of one of the families, and two copies were present among members of the other family. The CYP2D6L gene had an open reading frame and carried two mutations causing amino acid substitutions: one in exon 6, yielding an Arg-296-->Cys exchange and one in exon 9 causing Ser-486-->Thr. The MR of subjects carrying one copy of the CYP2D6L gene did not significantly differ from that of those with the wild-type gene, indicating that the structural alterations were not of importance of the catalytic properties of the gene product. Examination of the MR among subjects carrying wild-type CYP2D6, CYP2D6L, or deficient alleles revealed a relationship between the number of active genes and MR. The data show the principle of inherited amplification of an active gene. Furthermore, the finding of a specific haplotype with two or more active CYP2D6 genes allows genotyping for ultrarapid drug metabolizers. This genotyping could be of predictive value for individualized and more efficient drug therapy.

Alleles↗
PubMed1993

Genetic polymorphism of cytochrome P4502E1 in a Swedish population. Relationship to incidence of lung cancer.

Genetic polymorphism of CYP2E1 was investigated among 195 Swedish patients with lung cancer and 206 controls. Three different polymorphic sites were found, all in introns, using RFLP and the restriction enzymes DraI, RsaI and TaqI. The frequencies of the rare alleles were 0.08-0.18 and much lower than previously described among Japanese. No significant difference in distribution of the polymorphic alleles between controls and lung cancer patients was evident, in contrast to results of a previous Japanese study. However, examination of a polymorphic site in the 5'-flanking region, within a putative binding motif for the hepatic transcription factor HNF-1, revealed a significantly less frequent distribution of the mutated allele (c2) among the lung cancer patients as compared to controls. It is concluded that major interethnic differences exist in the genetic polymorphism of CYP2E1 and that people carrying the c2 allele might be at lower risk for developing lung cancer.

Base Sequence↗
PubMed1993

Polymorphic 2-hydroxylation of desipramine. A population and family study.

We have studied desipramine hydroxylation capacity, determined as the metabolic ratio of desipramine to 2-hydroxydesipramine in the urine after a single oral dose of 10 mg of desipramine, in 340 Swedish Caucasians, including the members of 45 two-generation families. Desipramine metabolic ratios were bimodally distributed among 237 unrelated subjects and 8% were poor metabolizers. There was a strong correlation between the metabolic ratios for desipramine and debrisoquine in 337 subjects phenotyped with both drugs and there was no dissociation between their capacities to hydroxylate desipramine and debrisoquine. Complex segregation analysis in the 45 families gave evidence for a major locus with incomplete recessivity (d = 0.14) controlling the 2-hydroxylation of desipramine. Similar results were obtained in segregation analysis for debrisoquine. There was evidence for linkage between the CYP2D6 gene and the gene regulating the hydroxylation of desipramine and debrisoquine. This study has provided unequivocal evidence that the capacity to 2-hydroxylate desipramine is polymorphic and under similar genetic control to the hydroxylation of debrisoquine.

Adolescent↗
PubMed1993

Debrisoquin and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents.

Debrisoquin and S-mephenytoin hydroxylation phenotypes were determined in 72 Spanish psychiatric patients treated with neuroleptic or antidepressant agents. One patient (1.4%) was classified as a poor metabolizer of S-mephenytoin. Between both neuroleptic- and antidepressant-treated patients, the distribution of the debrisoquin metabolic ratio was shifted toward higher values compared with 54 drug-free healthy subjects. Forty percent of patients treated with neuroleptics and 5% of patients treated with antidepressants were classified as poor metabolizers of debrisoquin. CYP2D6 genotype analysis in 36 neuroleptic-treated patients confirmed that the high metabolic ratios were attributable to inhibition of CYP2D6 and not to overrepresentation of subjects with poor metabolizer genotypes. In 48 selected Spanish drug-free subjects, CYP2D6 genotype predicted the phenotype with 95% accuracy. Neuroleptics and antidepressants interfere at therapeutic doses with phenotyping for CYP2D6 but not for S-mephenytoin hydroxylation capacity. In psychotropic-treated patients, genotyping provides a valuable tool for prediction of the CYP2D6 phenotype.

Adult↗
PubMed1993

Quinidine inhibition of debrisoquine S(+)-4- and 7-hydroxylations in Chinese of different CYP2D6 genotypes.

Pronounced differences in the CYP2D6 gene between Chinese and Caucasians have previously been described. There was a low frequency of detrimental mutations in the Chinese CYP2D6 gene causing the poor metabolizer (PM) phenotype. In contrast to Caucasians where the Xba I 44 kb allele is almost always associated with the PM phenotype, Chinese with the 44/44 kb RFLP pattern are extensive metabolizers (EM). In order to evaluate whether the debrisoquine hydroxylation seen in subjects with this haplotype is catalysed by a functionally similar enzyme to CYP2D6 or is catalysed by another type of P450 isozyme, product selectivity of the 4-hydroxylation was studied in 27 Chinese. The inhibition of CYP2D6 by quinidine was also investigated. In the 26 Chinese EM the S(+)-4-hydroxy enantiomer was found to be the major urinary metabolite of debrisoquine with an enantiomeric excess of 96.8-100%, which is similar to that in Caucasians. A correlation between the amount of S(+)-4-hydroxy and the minor 7-hydroxy metabolites excreted in urine (r = 0.72; p < 0.001) was seen. The amount of these two metabolites excreted was less in Chinese EM of debrisoquine with the 44/44 kb RFLP pattern, than in those with the wild type 29/29 kb pattern (p < 0.01). The stereoselectivity was very high in both groups. All Chinese homozygous for the 44 kb fragment (n = 5) were transformed to apparent PM after a single 100 mg dose of quinidine similarly to five Caucasian EM. Both the S(+)-4- and 7-hydroxylations of debrisoquine were inhibited by quinidine in both populations. This study shows that the cytochrome P450 catalysing the 4- and 7-hydroxylations of debrisoquine in Chinese EM has the same properties (product stereoselectivity and inhibition by quinidine) as the CYP2D6 in Caucasian EM.

Asian People↗