Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients
Clozapine (Clz) is an atypical antipsychotic, which its pharmacokinetics can be influenced by several factors. The CYP1A2 and CYP2C19, major enzymes implicated in Clz metabolism, present an interethnic variation on their activity caused by single nucleotide polymorphisms (SNPs). The present study in...
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| Veröffentlicht in: | The pharmacogenomics journal 2021-10, Vol.21 (5), p.551-558 |
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| creator | Ammar, Helmi Chadli, Zohra Mhalla, Ahmed Khouadja, Sabria Hannachi, Ibtissem Alshaikheid, Mohammed Slama, Ahlem Ben Fredj, Nadia Ben Fadhel, Najeh Ben Romdhane, Haifa Chaabane, Amel Boughattas, Naceur A. Gaha, Lotfi Zarrouk, Lazhar Aouam, Karim |
| description | Clozapine (Clz) is an atypical antipsychotic, which its pharmacokinetics can be influenced by several factors. The CYP1A2 and CYP2C19, major enzymes implicated in Clz metabolism, present an interethnic variation on their activity caused by single nucleotide polymorphisms (SNPs). The present study investigated the influence of genetic and nongenetic factors on Clz pharmacokinetics in a southern Mediterranean population. We included adult Tunisian schizophrenic patients having received Clz and undergone a therapeutic drug monitoring (TDM) of Clz by morning C0 monitoring. The genomic DNA was extracted using a salting-out procedure. CYP1A2*1F (rs762551;−163C>A), CYP1A2*1C (rs2069514;−3860 G>A) and CYP 2C19*2 (rs4244285; 681G>A) was analyzed using PCR-RFLP. Fifty-one patients were enrolled in the study. The mutant allele (
CYP1A2*1F
) was the most frequently detected (58.8%). For
CYP1A2*1F
, Clz dose-normalized (C0/D ratio) was as high as 1.28 ± 0.37 in CC versus 0.67 ± 0.32 ng mL
−1
per mg day
−1
in AA group (
p
A on the variation of Clz exposure in Tunisian schizophrenic patients. Considering its narrow therapeutic range, CYP1A2 genotyping combined with TDM of Clz may improve efficacy and safety of this drug. Further studies are needed to investigate this issue. |
| doi_str_mv | 10.1038/s41397-021-00231-x |
| format | Article |
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CYP1A2*1F
) was the most frequently detected (58.8%). For
CYP1A2*1F
, Clz dose-normalized (C0/D ratio) was as high as 1.28 ± 0.37 in CC versus 0.67 ± 0.32 ng mL
−1
per mg day
−1
in AA group (
p
< 0.001). The influence of genetic (
CYP1A2*1F, CYP1A2*1C
and
CYP2C19*2
) and nongenetic parameters (age, weight, gender, tobacco, coffee, and alcohol consumption) on the variation of the Clz C0/D ratio was investigated. Only the
CYP1A2*1
F
polymorphism correlates significantly with the Clz C0/D variation and could explain 24% of its variability. Our data support a critical role of the CYP1A2 −163C>A on the variation of Clz exposure in Tunisian schizophrenic patients. Considering its narrow therapeutic range, CYP1A2 genotyping combined with TDM of Clz may improve efficacy and safety of this drug. Further studies are needed to investigate this issue.</description><identifier>ISSN: 1470-269X</identifier><identifier>EISSN: 1473-1150</identifier><identifier>DOI: 10.1038/s41397-021-00231-x</identifier><identifier>PMID: 33731885</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>38/22 ; 45/77 ; 631/154/155 ; 631/154/436/434 ; Adult ; Alleles ; Antipsychotic Agents - blood ; Antipsychotic Agents - pharmacokinetics ; Antipsychotic Agents - therapeutic use ; Antipsychotics ; Biomedical and Life Sciences ; Biomedicine ; Chemical properties ; Clozapine ; Clozapine - blood ; Clozapine - pharmacokinetics ; Clozapine - therapeutic use ; Coffee ; CYP1A2 protein ; Cytochrome P-450 ; Cytochrome P-450 CYP1A2 - genetics ; Cytochrome P-450 CYP2C19 - genetics ; Cytochrome P450 ; Drug therapy ; Female ; Gene Expression ; Genetic aspects ; Genotyping ; Genotyping Techniques ; Human Genetics ; Humans ; Male ; Middle Aged ; Oncology ; Patients ; Pharmacokinetics ; Pharmacology, Experimental ; Pharmacotherapy ; Polymerase chain reaction ; Polymorphism, Single Nucleotide - genetics ; Psychopharmacology ; Restriction fragment length polymorphism ; Schizophrenia ; Schizophrenia - drug therapy ; Schizophrenia - genetics ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Therapeutic drug monitoring ; Tunisia ; Young Adult</subject><ispartof>The pharmacogenomics journal, 2021-10, Vol.21 (5), p.551-558</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-e96565610896d1d215d6fb30cc1ed1a38c0b1539f26600b1b281e4c8e643d4733</citedby><cites>FETCH-LOGICAL-c442t-e96565610896d1d215d6fb30cc1ed1a38c0b1539f26600b1b281e4c8e643d4733</cites><orcidid>0000-0002-6380-9339 ; 0000-0003-2636-6927 ; 0000-0002-9094-7243 ; 0000-0003-1500-7574</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33731885$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ammar, Helmi</creatorcontrib><creatorcontrib>Chadli, Zohra</creatorcontrib><creatorcontrib>Mhalla, Ahmed</creatorcontrib><creatorcontrib>Khouadja, Sabria</creatorcontrib><creatorcontrib>Hannachi, Ibtissem</creatorcontrib><creatorcontrib>Alshaikheid, Mohammed</creatorcontrib><creatorcontrib>Slama, Ahlem</creatorcontrib><creatorcontrib>Ben Fredj, Nadia</creatorcontrib><creatorcontrib>Ben Fadhel, Najeh</creatorcontrib><creatorcontrib>Ben Romdhane, Haifa</creatorcontrib><creatorcontrib>Chaabane, Amel</creatorcontrib><creatorcontrib>Boughattas, Naceur A.</creatorcontrib><creatorcontrib>Gaha, Lotfi</creatorcontrib><creatorcontrib>Zarrouk, Lazhar</creatorcontrib><creatorcontrib>Aouam, Karim</creatorcontrib><title>Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients</title><title>The pharmacogenomics journal</title><addtitle>Pharmacogenomics J</addtitle><addtitle>Pharmacogenomics J</addtitle><description>Clozapine (Clz) is an atypical antipsychotic, which its pharmacokinetics can be influenced by several factors. The CYP1A2 and CYP2C19, major enzymes implicated in Clz metabolism, present an interethnic variation on their activity caused by single nucleotide polymorphisms (SNPs). The present study investigated the influence of genetic and nongenetic factors on Clz pharmacokinetics in a southern Mediterranean population. We included adult Tunisian schizophrenic patients having received Clz and undergone a therapeutic drug monitoring (TDM) of Clz by morning C0 monitoring. The genomic DNA was extracted using a salting-out procedure. CYP1A2*1F (rs762551;−163C>A), CYP1A2*1C (rs2069514;−3860 G>A) and CYP 2C19*2 (rs4244285; 681G>A) was analyzed using PCR-RFLP. Fifty-one patients were enrolled in the study. The mutant allele (
CYP1A2*1F
) was the most frequently detected (58.8%). For
CYP1A2*1F
, Clz dose-normalized (C0/D ratio) was as high as 1.28 ± 0.37 in CC versus 0.67 ± 0.32 ng mL
−1
per mg day
−1
in AA group (
p
< 0.001). The influence of genetic (
CYP1A2*1F, CYP1A2*1C
and
CYP2C19*2
) and nongenetic parameters (age, weight, gender, tobacco, coffee, and alcohol consumption) on the variation of the Clz C0/D ratio was investigated. Only the
CYP1A2*1
F
polymorphism correlates significantly with the Clz C0/D variation and could explain 24% of its variability. Our data support a critical role of the CYP1A2 −163C>A on the variation of Clz exposure in Tunisian schizophrenic patients. Considering its narrow therapeutic range, CYP1A2 genotyping combined with TDM of Clz may improve efficacy and safety of this drug. Further studies are needed to investigate this issue.</description><subject>38/22</subject><subject>45/77</subject><subject>631/154/155</subject><subject>631/154/436/434</subject><subject>Adult</subject><subject>Alleles</subject><subject>Antipsychotic Agents - blood</subject><subject>Antipsychotic Agents - pharmacokinetics</subject><subject>Antipsychotic Agents - therapeutic use</subject><subject>Antipsychotics</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Chemical properties</subject><subject>Clozapine</subject><subject>Clozapine - blood</subject><subject>Clozapine - pharmacokinetics</subject><subject>Clozapine - therapeutic use</subject><subject>Coffee</subject><subject>CYP1A2 protein</subject><subject>Cytochrome P-450</subject><subject>Cytochrome P-450 CYP1A2 - genetics</subject><subject>Cytochrome P-450 CYP2C19 - genetics</subject><subject>Cytochrome P450</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Genetic aspects</subject><subject>Genotyping</subject><subject>Genotyping Techniques</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Oncology</subject><subject>Patients</subject><subject>Pharmacokinetics</subject><subject>Pharmacology, Experimental</subject><subject>Pharmacotherapy</subject><subject>Polymerase chain reaction</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Psychopharmacology</subject><subject>Restriction fragment length polymorphism</subject><subject>Schizophrenia</subject><subject>Schizophrenia - drug therapy</subject><subject>Schizophrenia - genetics</subject><subject>Single nucleotide polymorphisms</subject><subject>Single-nucleotide polymorphism</subject><subject>Therapeutic drug monitoring</subject><subject>Tunisia</subject><subject>Young Adult</subject><issn>1470-269X</issn><issn>1473-1150</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU9r3DAQxUVJaP71C_RQBDk71UiybB_D0iaBhV4SyE1o5fGuNrbkSjYk-fRVd9M2hRDmoEF6vzcaHiGfgV0AE_XXJEE0VcE4FIxxAcXjB3IMshIFQMkOdj0ruGruj8hJSlvGQEFVfyRHQlQC6ro8Jm7RO--s6anxLV2jx8lZ6nzXz-it82vaGTuFmGjw1Pbh2YzOIx03Jg7Ghge3A1Im6O3sXXLG02Q37jmMm4jZmY5mcuindEYOO9Mn_PRynpK7799uF9fF8sfVzeJyWVgp-VRgo8pcwOpGtdByKFvVrQSzFrAFI2rLVlCKpuNKsdyueA0obY1KijbvLk7J-d53jOHnjGnS2zBHn0dqXlayEZzJV6q16VHnfcMUjR1csvpSVUoIqaomqy7eUOVqcXA2eOxcvv8P4HvAxpBSxE6P0Q0mPmlg-ndoeh-azqHpXWj6MUNfXn48rwZs_yJ_UsoCsRek_OTXGP-t9I7tLwukolM</recordid><startdate>20211001</startdate><enddate>20211001</enddate><creator>Ammar, Helmi</creator><creator>Chadli, Zohra</creator><creator>Mhalla, Ahmed</creator><creator>Khouadja, Sabria</creator><creator>Hannachi, Ibtissem</creator><creator>Alshaikheid, Mohammed</creator><creator>Slama, Ahlem</creator><creator>Ben Fredj, Nadia</creator><creator>Ben Fadhel, Najeh</creator><creator>Ben Romdhane, Haifa</creator><creator>Chaabane, Amel</creator><creator>Boughattas, Naceur A.</creator><creator>Gaha, Lotfi</creator><creator>Zarrouk, Lazhar</creator><creator>Aouam, Karim</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0002-6380-9339</orcidid><orcidid>https://orcid.org/0000-0003-2636-6927</orcidid><orcidid>https://orcid.org/0000-0002-9094-7243</orcidid><orcidid>https://orcid.org/0000-0003-1500-7574</orcidid></search><sort><creationdate>20211001</creationdate><title>Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients</title><author>Ammar, Helmi ; Chadli, Zohra ; Mhalla, Ahmed ; Khouadja, Sabria ; Hannachi, Ibtissem ; Alshaikheid, Mohammed ; Slama, Ahlem ; Ben Fredj, Nadia ; Ben Fadhel, Najeh ; Ben Romdhane, Haifa ; Chaabane, Amel ; Boughattas, Naceur A. ; Gaha, Lotfi ; Zarrouk, Lazhar ; Aouam, Karim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-e96565610896d1d215d6fb30cc1ed1a38c0b1539f26600b1b281e4c8e643d4733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>38/22</topic><topic>45/77</topic><topic>631/154/155</topic><topic>631/154/436/434</topic><topic>Adult</topic><topic>Alleles</topic><topic>Antipsychotic Agents - blood</topic><topic>Antipsychotic Agents - pharmacokinetics</topic><topic>Antipsychotic Agents - therapeutic use</topic><topic>Antipsychotics</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Chemical properties</topic><topic>Clozapine</topic><topic>Clozapine - blood</topic><topic>Clozapine - pharmacokinetics</topic><topic>Clozapine - therapeutic use</topic><topic>Coffee</topic><topic>CYP1A2 protein</topic><topic>Cytochrome P-450</topic><topic>Cytochrome P-450 CYP1A2 - genetics</topic><topic>Cytochrome P-450 CYP2C19 - genetics</topic><topic>Cytochrome P450</topic><topic>Drug therapy</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Genetic aspects</topic><topic>Genotyping</topic><topic>Genotyping Techniques</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Oncology</topic><topic>Patients</topic><topic>Pharmacokinetics</topic><topic>Pharmacology, Experimental</topic><topic>Pharmacotherapy</topic><topic>Polymerase chain reaction</topic><topic>Polymorphism, Single Nucleotide - 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The CYP1A2 and CYP2C19, major enzymes implicated in Clz metabolism, present an interethnic variation on their activity caused by single nucleotide polymorphisms (SNPs). The present study investigated the influence of genetic and nongenetic factors on Clz pharmacokinetics in a southern Mediterranean population. We included adult Tunisian schizophrenic patients having received Clz and undergone a therapeutic drug monitoring (TDM) of Clz by morning C0 monitoring. The genomic DNA was extracted using a salting-out procedure. CYP1A2*1F (rs762551;−163C>A), CYP1A2*1C (rs2069514;−3860 G>A) and CYP 2C19*2 (rs4244285; 681G>A) was analyzed using PCR-RFLP. Fifty-one patients were enrolled in the study. The mutant allele (
CYP1A2*1F
) was the most frequently detected (58.8%). For
CYP1A2*1F
, Clz dose-normalized (C0/D ratio) was as high as 1.28 ± 0.37 in CC versus 0.67 ± 0.32 ng mL
−1
per mg day
−1
in AA group (
p
< 0.001). The influence of genetic (
CYP1A2*1F, CYP1A2*1C
and
CYP2C19*2
) and nongenetic parameters (age, weight, gender, tobacco, coffee, and alcohol consumption) on the variation of the Clz C0/D ratio was investigated. Only the
CYP1A2*1
F
polymorphism correlates significantly with the Clz C0/D variation and could explain 24% of its variability. Our data support a critical role of the CYP1A2 −163C>A on the variation of Clz exposure in Tunisian schizophrenic patients. Considering its narrow therapeutic range, CYP1A2 genotyping combined with TDM of Clz may improve efficacy and safety of this drug. Further studies are needed to investigate this issue.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33731885</pmid><doi>10.1038/s41397-021-00231-x</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-6380-9339</orcidid><orcidid>https://orcid.org/0000-0003-2636-6927</orcidid><orcidid>https://orcid.org/0000-0002-9094-7243</orcidid><orcidid>https://orcid.org/0000-0003-1500-7574</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1470-269X |
| ispartof | The pharmacogenomics journal, 2021-10, Vol.21 (5), p.551-558 |
| issn | 1470-269X 1473-1150 |
| language | eng |
| recordid | cdi_proquest_journals_2574932043 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | 38/22 45/77 631/154/155 631/154/436/434 Adult Alleles Antipsychotic Agents - blood Antipsychotic Agents - pharmacokinetics Antipsychotic Agents - therapeutic use Antipsychotics Biomedical and Life Sciences Biomedicine Chemical properties Clozapine Clozapine - blood Clozapine - pharmacokinetics Clozapine - therapeutic use Coffee CYP1A2 protein Cytochrome P-450 Cytochrome P-450 CYP1A2 - genetics Cytochrome P-450 CYP2C19 - genetics Cytochrome P450 Drug therapy Female Gene Expression Genetic aspects Genotyping Genotyping Techniques Human Genetics Humans Male Middle Aged Oncology Patients Pharmacokinetics Pharmacology, Experimental Pharmacotherapy Polymerase chain reaction Polymorphism, Single Nucleotide - genetics Psychopharmacology Restriction fragment length polymorphism Schizophrenia Schizophrenia - drug therapy Schizophrenia - genetics Single nucleotide polymorphisms Single-nucleotide polymorphism Therapeutic drug monitoring Tunisia Young Adult |
| title | Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T14%3A05%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Clinical%20and%20genetic%20influencing%20factors%20on%20clozapine%20pharmacokinetics%20in%20Tunisian%20schizophrenic%20patients&rft.jtitle=The%20pharmacogenomics%20journal&rft.au=Ammar,%20Helmi&rft.date=2021-10-01&rft.volume=21&rft.issue=5&rft.spage=551&rft.epage=558&rft.pages=551-558&rft.issn=1470-269X&rft.eissn=1473-1150&rft_id=info:doi/10.1038/s41397-021-00231-x&rft_dat=%3Cgale_proqu%3EA676334679%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2574932043&rft_id=info:pmid/33731885&rft_galeid=A676334679&rfr_iscdi=true |