Infant Dextromethorphan and Dextrorphan Exposure via Breast Milk From Mothers Who Are CYP2D6 Extensive Metabolizers

Shum, Sara; Yadav, Aprajita S; Fay, Emily; Moreni, Sue L.; Mao, Jennie; Czuba, Lindsay C.; Wang, Celine; Isoherranen, Nina; Hébert, Mary F.

doi:10.1002/jcph.2012

Cited by 4 publications

(10 citation statements)

References 35 publications

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“…All enrolled participants were between 18 and 50 years of age and were CYP2D6 extensive metabolizers based on the genotype originally selected to take part in a larger study assessing the effect of retinoids on CYP2D6 enzyme activity in pregnancy [ 12 ]. Subjects provided written informed consent to participate in this study.…”

Section: Methodsmentioning

confidence: 99%

“…A single blood sample from each subject was collected on each study day, at approximately 10:00 a.m. and approximately 1 h following the start of breakfast. This sampling window was chosen in accordance with the needs of the larger study on CYP2D6 metabolism [ 12 ]. Blood was collected into EDTA vacutainer tubes, placed on ice and then the plasma separated via centrifugation at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

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The Effects of Pregnancy on Amino Acid Levels and Nitrogen Disposition

et al. 2023

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Limited data are available on the effects of pregnancy on the maternal metabolome. Therefore, the objective of this study was to use metabolomics analysis to determine pathways impacted by pregnancy followed by targeted confirmatory analysis to provide more powerful conclusions about metabolic alterations during pregnancy. Forty-seven pregnant women, 18–50 years of age were included in this study, with each subject serving as their own control. Plasma samples were collected between 25 and 28 weeks gestation and again ≥3 months postpartum for metabolomics analysis utilizing an HILIC/UHPLC/MS/MS assay with confirmatory targeted specific concentration analysis for 10 of the significantly altered amino acids utilizing an LC/MS assay. Principle component analysis (PCA) on metabolomics data clearly separated pregnant and postpartum groups and identified outliers in a preliminary assessment. Of the 980 metabolites recorded, 706 were determined to be significantly different between pregnancy and postpartum. Pathway analysis revealed three significantly impacted pathways, arginine biosynthesis (p = 2 × 10−5 and FDR = 1 × 10−3), valine, leucine, and isoleucine metabolism (p = 2 × 10−5 and FDR = 2 × 10−3), and xanthine metabolism (p = 4 × 10−5 and FDR = 4 × 10−3). Of these we focused analysis on arginine biosynthesis and branched-chain amino acid (BCAA) metabolism due to their clinical importance and interconnected roles in amino acid metabolism. In the confirmational analysis, 7 of 10 metabolites were confirmed as significant and all 10 confirmed the direction of change of concentrations observed in the metabolomics analysis. The data support an alteration in urea nitrogen disposition and amino acid metabolism during pregnancy. These changes could also impact endogenous nitric oxide production and contribute to diseases of pregnancy. This study provides evidence for changes in both the ammonia-urea nitrogen and the BCAA metabolism taking place during pregnancy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The Effects of Pregnancy on Amino Acid Levels and Nitrogen Disposition

et al. 2023

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“…CYP2D6 genotype assays were performed as previously described using a StepOnePlus time polymerase chain reaction (PCR) instrument following the manufacturer's recommended protocols (Applied Biosystems, Waltham, Massachusetts) 28 . The samples were genotyped for 9 core single‐nucleotide polymorphisms (SNPs), and the CYP2D6 genotype was assigned to each allele as previously described by our group 31 . The CYP2D6 genotype was translated into the activity score (AS) and expected phenotype designation based on previously described methods 32 .…”

Section: Methodsmentioning

confidence: 99%

“…28 The samples were genotyped for 9 core single-nucleotide polymorphisms (SNPs), and the CYP2D6 genotype was assigned to each allele as previously described by our group. 31 The CYP2D6 genotype was translated into the activity score (AS) and expected phenotype designation based on previously described methods. 32 The CYP2D6 AS for each participant was calculated by the summation of the assigned values to each allele.…”

Section: Cyp2d6 Genotypingmentioning

confidence: 99%

Impact of Pregnancy and Vitamin A Supplementation on CYP2D6 Activity

Amaeze

Czuba

Yadav

et al. 2022

The Journal of Clinical Pharma

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The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty-seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3-hydroxymorphinan (3HM), were determined from a 2-hour post-dose plasma sample and cumulative 4-hour urine sample using liquid chromatography-mass spectrometry. Change in CYP2D6 activity was assessed using DX/DM plasma and urine metabolic ratios. The activity change in CYP3A was also assessed using the 3HM/DM urine metabolic ratio. The DX/DM urine ratio was significantly higher (43%) in pregnancy compared with postpartum (P = .03), indicating increased CYP2D6 activity. The DX/DM plasma ratio was substantially higher in the participants,with an activity score of 1.0 during pregnancy (P = .04) compared with postpartum.The 3HM/DM urinary ratio was significantly higher (92%) during pregnancy, reflecting increased CYP3A activity (P = .02). Vitamin A supplementation did not change CYP2D6 activity during pregnancy; however, plasma all-trans retinoic acid (atRA) concentrations were positively correlated with increased CYP2D6 activity during pregnancy and postpartum. Further research is needed to elucidate the mechanisms of increased CYP2D6 activity during pregnancy.

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“…CYP2D6 genotypes and activity scores (ASs) were determined using previously published genotyping strategy and methods. [21][22][23] The CYP2D6 ASs were calculated by the summation of values that were assigned to each allele. CYP2D6 metabolizer phenotypes were assigned with the corresponding AS values: poor (AS = 0), intermediate (AS = 0.5), extensive (AS = 1-2) and ultrarapid (AS > 2).…”

Section: Cyp2d6 and Cyp3a5 Genotypingmentioning

confidence: 99%

Effect of isotretinoin on CYP2D6 and CYP3A activity in patients with severe acne

Zhao,

Vary,

Yadav

et al. 2023

Brit J Clinical Pharma

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AimPreviously, retinoids have decreased CYP2D6 mRNA expression in vitro and induced CYP3A4 in vitro and in vivo. This study aimed to determine whether isotretinoin administration changes CYP2D6 and CYP3A activities in patients with severe acne.MethodsThirty‐three patients (22 females and 11 males, 23.5 ± 6.0 years old) expected to receive isotretinoin treatment completed the study. All participants were genotyped for CYP2D6 and CYP3A5. Participants received dextromethorphan (DM) 30 mg orally as a dual‐probe substrate of CYP2D6 and CYP3A activity at two study timepoints: pre‐isotretinoin treatment and with isotretinoin for at least one week. The concentrations of isotretinoin, DM and their metabolites were measured in 2‐hour post‐dose plasma samples and in cumulative 0–4‐hour urine collections using liquid chromatography‐mass spectrometry.ResultsIn CYP2D6 extensive metabolizers, urinary dextrorphan (DX)/DM metabolic ratio (MR) (CYP2D6 activity marker) was numerically, but not significantly lower with isotretinoin administration compared to pre‐isotretinoin (geometric mean ratio [GMR] [90% confidence interval (CI)]: 0.78 [0.55, 1.11]). The urinary 3‐hydroxymorphinan (3HM)/DX MR (CYP3A activity marker) was increased (GMR: 1.18 [1.03, 1.35]) and the urinary DX‐O‐glucuronide/DX MR (proposed UGT2B marker) was increased (GMR: 1.22 [1.06, 1.39]) with isotretinoin administration compared to pre‐isotretinoin.ConclusionAdministration of isotretinoin did not significantly reduce CYP2D6 activity in extensive metabolizers, suggesting that the predicted downregulation of CYP2D6 based on in vitro data does not translate into humans. We observed a modest increase in CYP3A activity (predominantly CYP3A4) with isotretinoin treatment. The data also suggest dextrorphan glucuronidation is increased following isotretinoin administration.

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Infant Dextromethorphan and Dextrorphan Exposure via Breast Milk From Mothers Who Are CYP2D6 Extensive Metabolizers

Cited by 4 publications

References 35 publications

The Effects of Pregnancy on Amino Acid Levels and Nitrogen Disposition

The Effects of Pregnancy on Amino Acid Levels and Nitrogen Disposition

Impact of Pregnancy and Vitamin A Supplementation on CYP2D6 Activity

Effect of isotretinoin on CYP2D6 and CYP3A activity in patients with severe acne

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