10-hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes*

Dalén, Per; Dahl, Marja­‐Liisa; Ruiz, María Luisa Bernal; Nordin, Jan; Bertilsson, Leif

doi:10.1016/s0009-9236(98)90040-6

Cited by 258 publications

(156 citation statements)

References 28 publications

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“…On the contrary, multiple copies of *2 gene result in increased activity of CYP2D6 and clearance of nortriptyline. The apparent oral clearances of nortriptyline were increased in the subjects with two or three functional CYP2D6 genes (Dalén et al, 1998). However, those with *2 allele did not result in increased or decreased activity of CYP2D6 at least in our data.…”

Section: Inter-individual Variations Of Plasma Concentrations Of Hal contrasting

confidence: 41%

Effect of CYP2D6 Genotypes on the Metabolism of Haloperidol in a Japanese Psychiatric Population

Someya

Saito

Suzuki

et al. 2003

Neuropsychopharmacol

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We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/ CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14 7 0.69 ng/ml/mg) and RHAL (1.10 7 1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL ¼ 0.68 7 0.31 ng/ml/mg, RHAL ¼ 0.28 7 0.37 ng/ml/mg), those with one CYP2D6*10 (HAL ¼ 0.70 7 0.23 ng/ ml/mg, RHAL ¼ 0.31 7 0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL ¼ 0.69 7 0.14 ng/ml/mg, RHAL ¼ 0.40 7 0.09 ng/ ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (o10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43 7 0.23 ng/ml/mg, 0.34 7 0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18 7 0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.

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Section: Inter-individual Variations Of Plasma Concentrations Of Hal contrasting

confidence: 41%

Effect of CYP2D6 Genotypes on the Metabolism of Haloperidol in a Japanese Psychiatric Population

Someya

Saito

Suzuki

et al. 2003

Neuropsychopharmacol

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“…CYP2D6 gene is highly polymorphic; hitherto more than one hundred allelic variants were identified, a number of [3,4]. Due to the wide range of CYP2D6 enzyme activity within the population, the patients can be divided into four metabolizer groups: poor (PM), intermediate (IM), extensive (EM) and ultra-rapid metabolizers (UM) [5].…”

Section: Introductionmentioning

confidence: 99%

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

Kiss

Tóth

Juhasz

et al. 2018

Microchemical Journal

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Hungary Highlights• CYP2D6 genotype-based phenotype estimation is of particular importance to personalized medication strategy.• The non-sequencing genotyping platform identified the most frequent CYP2D6 allelic variants (in 67% of the donors).• The gain-of-function mutation (-1584C>G) could explain the underestimation of CYP2D6 genotype-based prediction.• Some rare loss-of-function mutations that were not captured, could result in overestimation of CYP2D6 activity prediction.• CYP2D6 phenotype overestimation may also come from external factors modifying CYP2D6 activity or altering hepatic function.• A comprehensive genotyping and consideration of phenoconversion can improve the genotype-based CYP2D6 phenotype prediction. 2 AbstractGenetic polymorphism of cytochrome P450s results in clinically significant modifications in patients' drug metabolizing capacities. CYP2D6 has a crucial role in the elimination of several clinically important drugs (antiarrhythmics, beta-adrenergic blockers, psychopharmacons and analgesics); however, the prediction of the phenotypic appearance of CYP2D6 is a challenge. Since single nucleotide polymorphisms and gene copy number variations (gene deletion and multiplication) frequently occur in CYP2D6 gene, CYP2D6 activity particularly depends on the genetic factors.Microsomal CYP2D6 activities (dextromethorphan O-demethylation) and CYP2D6 genotypes for the most frequent allelic variants (CYP2D6*3, *4, *5, *6, *10, *41 and duplication) were determined in 128 human liver samples derived from Hungarian organ donors. Substantial inter-individual variations were observed in CYP2D6 metabolic activities that were successfully predicted from the CYP2D6 genotypes in 67% of the donors. The underestimation of CYP2D6 phenotypes in 12.5% of the donors was assumed to be originated from the overlapping ranges of CYP2D6 activity among similar diplotypes or from the presence of -1584C>G in the promoter region evoking increased transcription of the wild-type CYP2D6 allele. In an appreciable number of donors (20.3%), the genotype-based CYP2D6 phenotype prediction was overestimated because of the rare CYP2D6 allelic variants which were not included in our genotyping platform or some external factors that could alter CYP2D6 activity (medication with CYP2D6 substrate/inhibitor) and hepatic function (Augmentin therapy, chronic alcohol consumption).In conclusion, CYP2D6 genotyping for the most frequent allelic variants was able to reliably predict CYP2D6 phenotypes in most donors; however, the external factors modifying the phenotypic appearance of CYP2D6 had to be taken into account. Personalized medication strategy should include monitoring of CYP2D6 genotype in a more comprehensive manner 3 and should take external factors into consideration for an appropriate prediction of CYP2D6 metabolizing capacity.

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“…Indeed, gender was a stronger predictor of nortriptyline concentration than was CYP2D6 genotype. Dalen et al (1998) gave 21 healthy Caucasian subjects, ages 18 to 48, single doses of nortriptyline (other medications unspecified) and measured pharmacokinetics over the next 168 hours. They found significant corrrelations between CYP2D6 genotype and nortriptyline clearance.…”

Section: Discussionmentioning

confidence: 99%

“…However, there are numerous CYP2D6 mutations that affect drug metabolism, and genotyping using conventional methods such as restriction isotyping is labor intensive involving multiple polymerase chain reactions, restriction enzyme digestions, and separations of digested DNA fragments by gel electrophoresis (Sachse et al 1997). Further, all prior studies of CYP2D6 genotype and nortriptyline levels have utilized single dose pharmacokinetic designs or clinical samples of predominantly younger patients taking few concurrent medications (Dahl et al 1996;Dalen et al 1998;Yue et al 1998;Morita et al 2000). Results from these prior studies may not be applicable to geriatric patients prescribed nortriptyline in clinical settings where large numbers of concurrent medications are also utilized that may alter debrisoquine hydroxylase activity.…”

mentioning

confidence: 99%

CYP2D6 Genotyping with Oligonucleotide Microarrays and Nortriptyline Concentrations in Geriatric Depression

Murphy

Pollock

Kirshner

et al. 2001

Neuropsychopharmacology

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10-hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes*

Cited by 258 publications

References 28 publications

Effect of CYP2D6 Genotypes on the Metabolism of Haloperidol in a Japanese Psychiatric Population

Effect of CYP2D6 Genotypes on the Metabolism of Haloperidol in a Japanese Psychiatric Population

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

CYP2D6 Genotyping with Oligonucleotide Microarrays and Nortriptyline Concentrations in Geriatric Depression

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