TY  - JOUR
AU  - Lenk, Hasan Çağın
AU  - Løvsletten Smith, Robert
AU  - O'Connell, Kevin
AU  - Jukić, Marin
AU  - Kringen, Marianne Kristiansen
AU  - Andreassen, Ole
AU  - Ingelman-Sundberg, Magnus
AU  - Molden, Espen
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4290
AB  - Clinical response of clozapine is closely associated with serum concentration. Although tobacco smoking is the key environmental factor underlying interindividual variability in clozapine metabolism, recent genome-wide studies suggest that CYP1A and NFIB genetic variants may also be of significant importance, but their quantitative impact is unclear. We investigated the effects of the rs2472297 C>T (CYP1A) and rs28379954 T>C (NFIB) polymorphisms on serum concentrations in smokers and nonsmokers. The study retrospectively included 526 patients with known smoking habits (63.7% smokers) from a therapeutic drug monitoring service in Norway. Clozapine dose-adjusted concentrations (C/D) and patient proportions with subtherapeutic levels (<1070 nmol/L) were compared between CYP1A/NFIB variant allele carriers and homozygous wild-type carriers (noncarriers), in both smokers and nonsmokers. Clozapine C/D was reduced in patients carrying CYP1A-T and NFIB-C variants versus noncarriers, both among smokers (−48%; p < 0.0001) and nonsmokers (−35%; p = 0.028). Patients who smoke carrying CYP1A-T and NFIB-C variants had a 66% reduction in clozapine C/D versus nonsmoking noncarriers (p < 0.0001). The patient proportion with subtherapeutic levels was 2.9-fold higher in patients who smoke carrying NFIB-C and CYP1A-T variants versus nonsmoking noncarriers (p < 0.0001). In conclusion, CYP1A and NFIB variants have significant and additive impact on clozapine dose requirements for reaching target serum concentrations. Patients who smoke carrying the studied CYP1A and NFIB variants, comprising 2.5% of the study population, may need threefold higher doses to prevent risk of clozapine undertreatment. The results suggest that pre-emptive genotyping of NFIB and CYP1A may be utilized to guide clozapine dosing and improve clinical outcomes in patients with treatment-resistant schizophrenia. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PB  - John Wiley and Sons Inc
T2  - Clinical and Translational Science
T1  - Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits
DO  - 10.1111/cts.13422
ER  - 

@article{
author = "Lenk, Hasan Çağın and Løvsletten Smith, Robert and O'Connell, Kevin and Jukić, Marin and Kringen, Marianne Kristiansen and Andreassen, Ole and Ingelman-Sundberg, Magnus and Molden, Espen",
year = "2022",
abstract = "Clinical response of clozapine is closely associated with serum concentration. Although tobacco smoking is the key environmental factor underlying interindividual variability in clozapine metabolism, recent genome-wide studies suggest that CYP1A and NFIB genetic variants may also be of significant importance, but their quantitative impact is unclear. We investigated the effects of the rs2472297 C>T (CYP1A) and rs28379954 T>C (NFIB) polymorphisms on serum concentrations in smokers and nonsmokers. The study retrospectively included 526 patients with known smoking habits (63.7% smokers) from a therapeutic drug monitoring service in Norway. Clozapine dose-adjusted concentrations (C/D) and patient proportions with subtherapeutic levels (<1070 nmol/L) were compared between CYP1A/NFIB variant allele carriers and homozygous wild-type carriers (noncarriers), in both smokers and nonsmokers. Clozapine C/D was reduced in patients carrying CYP1A-T and NFIB-C variants versus noncarriers, both among smokers (−48%; p < 0.0001) and nonsmokers (−35%; p = 0.028). Patients who smoke carrying CYP1A-T and NFIB-C variants had a 66% reduction in clozapine C/D versus nonsmoking noncarriers (p < 0.0001). The patient proportion with subtherapeutic levels was 2.9-fold higher in patients who smoke carrying NFIB-C and CYP1A-T variants versus nonsmoking noncarriers (p < 0.0001). In conclusion, CYP1A and NFIB variants have significant and additive impact on clozapine dose requirements for reaching target serum concentrations. Patients who smoke carrying the studied CYP1A and NFIB variants, comprising 2.5% of the study population, may need threefold higher doses to prevent risk of clozapine undertreatment. The results suggest that pre-emptive genotyping of NFIB and CYP1A may be utilized to guide clozapine dosing and improve clinical outcomes in patients with treatment-resistant schizophrenia. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.",
publisher = "John Wiley and Sons Inc",
journal = "Clinical and Translational Science",
title = "Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits",
doi = "10.1111/cts.13422"
}

Lenk, H. Ç., Løvsletten Smith, R., O'Connell, K., Jukić, M., Kringen, M. K., Andreassen, O., Ingelman-Sundberg, M.,& Molden, E.. (2022). Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits. in Clinical and Translational Science
John Wiley and Sons Inc..
https://doi.org/10.1111/cts.13422

Lenk HÇ, Løvsletten Smith R, O'Connell K, Jukić M, Kringen MK, Andreassen O, Ingelman-Sundberg M, Molden E. Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits. in Clinical and Translational Science. 2022;.
doi:10.1111/cts.13422 .

Lenk, Hasan Çağın, Løvsletten Smith, Robert, O'Connell, Kevin, Jukić, Marin, Kringen, Marianne Kristiansen, Andreassen, Ole, Ingelman-Sundberg, Magnus, Molden, Espen, "Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits" in Clinical and Translational Science (2022),
https://doi.org/10.1111/cts.13422 . .

TY  - JOUR
AU  - Lenk, Hasan Çağın
AU  - Klöditz, Katharina
AU  - Johansson, Inger
AU  - Løvsletten Smith, Robert
AU  - Jukić, Marin
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4075
AB  - The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo.
PB  - John Wiley and Sons Inc
T2  - Clinical Pharmacology and Therapeutics
T1  - The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients
DO  - 10.1002/cpt.2571
ER  - 

@article{
author = "Lenk, Hasan Çağın and Klöditz, Katharina and Johansson, Inger and Løvsletten Smith, Robert and Jukić, Marin and Molden, Espen and Ingelman-Sundberg, Magnus",
year = "2022",
abstract = "The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo.",
publisher = "John Wiley and Sons Inc",
journal = "Clinical Pharmacology and Therapeutics",
title = "The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients",
doi = "10.1002/cpt.2571"
}

Lenk, H. Ç., Klöditz, K., Johansson, I., Løvsletten Smith, R., Jukić, M., Molden, E.,& Ingelman-Sundberg, M.. (2022). The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients. in Clinical Pharmacology and Therapeutics
John Wiley and Sons Inc..
https://doi.org/10.1002/cpt.2571

Lenk HÇ, Klöditz K, Johansson I, Løvsletten Smith R, Jukić M, Molden E, Ingelman-Sundberg M. The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients. in Clinical Pharmacology and Therapeutics. 2022;.
doi:10.1002/cpt.2571 .

Lenk, Hasan Çağın, Klöditz, Katharina, Johansson, Inger, Løvsletten Smith, Robert, Jukić, Marin, Molden, Espen, Ingelman-Sundberg, Magnus, "The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients" in Clinical Pharmacology and Therapeutics (2022),
https://doi.org/10.1002/cpt.2571 . .