Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure
Summary What is known and objective Hydralazine is an inhibitor of DNA methyltransferases, whereas valproate interferes with histone deacetylation. In combination, they show a marked synergism in reducing tumour growth as well as development of metastasis and inducing cell differentiation. Hydralazi...
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| Veröffentlicht in: | Journal of clinical pharmacy and therapeutics 2014-08, Vol.39 (4), p.368-375 |
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| creator | Garcés-Eisele, S. J. Cedillo-Carvallo, B. Reyes-Núñez, V. Estrada-Marín, L. Vázquez-Pérez, R. Juárez-Calderón, M. Guzmán-García, M. O. Dueñas-González, A. Ruiz-Argüelles, A. |
| description | Summary
What is known and objective
Hydralazine is an inhibitor of DNA methyltransferases, whereas valproate interferes with histone deacetylation. In combination, they show a marked synergism in reducing tumour growth as well as development of metastasis and inducing cell differentiation. Hydralazine is metabolized by the highly polymorphic N‐acetyltransferase 2. The current pilot study was performed to analyse the pharmacokinetic parameters of a single dose of hydralazine in 24 h (one tablet with 83 mg for slow acetylators and one tablet with 182 mg for fast acetylators) and three fixed doses of valproate (one tablet of controlled liberation with 700 mg every 8 h) in healthy genetically selected volunteers. Selection was performed based on their NAT2 activity as deduced from their genotype.
Methods
An open label non‐randomized single arm study was conducted in two groups of six healthy volunteers of both genders aged 20–45 years with a body mass index 22·2–26·9 which were classified as fast or slow acetylators after genotyping 3 SNPs that cover 99·9% of the NAT2 variants in the Mexican population. Blood samples were collected predose and serially post‐dose in an interval of 48 h. Hydralazine and valproate concentrations were determined by ultra‐high performance liquid chromatography (UPLC) coupled to tandem mass spectroscopy (MS/MS).
Results and discussion
The AUC0–48 h and Cmax of hydralazine were almost identical (1410 ± 560 vs. 1446 ± 509 ng h/mL and 93·4 ± 16·7 vs. 112·5 ± 42·1 ng/mL) in both groups with NAT2 genotype‐adjusted doses, whereas the multidose parameters of valproate were not significantly affected neither by the selection of the NAT2 genotype (AUC0–48 h 2064 ± 455 vs. 1896 ± 185 μg h/mL; Cmax 96·4 ± 21·1 vs. 88·8 ± 7·2 μg/mL, for the fast and slow acetylators, respectively) nor the co‐administration of 83 or 182 mg of hydralazine.
What is new and conclusion
Comparable hydralazine exposures (differences in AUC0–inf of only 7%) were observed in this study with genetic selection of volunteers and concomitant dose adjustment. However, the conclusions have yet to be confirmed with a full‐powered 2 × 2 crossover study.
Hydralazine is extensively metabolized by the highly polymorphic N‐acetyltransferase 2, which complicates its correct dosing, and increases the costs of bioavailability or bioequivalence studies. We selected two groups of volunteers with genetically defined NAT2 activities and administered a single acetylator activity‐adjusted d |
| doi_str_mv | 10.1111/jcpt.12155 |
| format | Article |
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What is known and objective
Hydralazine is an inhibitor of DNA methyltransferases, whereas valproate interferes with histone deacetylation. In combination, they show a marked synergism in reducing tumour growth as well as development of metastasis and inducing cell differentiation. Hydralazine is metabolized by the highly polymorphic N‐acetyltransferase 2. The current pilot study was performed to analyse the pharmacokinetic parameters of a single dose of hydralazine in 24 h (one tablet with 83 mg for slow acetylators and one tablet with 182 mg for fast acetylators) and three fixed doses of valproate (one tablet of controlled liberation with 700 mg every 8 h) in healthy genetically selected volunteers. Selection was performed based on their NAT2 activity as deduced from their genotype.
Methods
An open label non‐randomized single arm study was conducted in two groups of six healthy volunteers of both genders aged 20–45 years with a body mass index 22·2–26·9 which were classified as fast or slow acetylators after genotyping 3 SNPs that cover 99·9% of the NAT2 variants in the Mexican population. Blood samples were collected predose and serially post‐dose in an interval of 48 h. Hydralazine and valproate concentrations were determined by ultra‐high performance liquid chromatography (UPLC) coupled to tandem mass spectroscopy (MS/MS).
Results and discussion
The AUC0–48 h and Cmax of hydralazine were almost identical (1410 ± 560 vs. 1446 ± 509 ng h/mL and 93·4 ± 16·7 vs. 112·5 ± 42·1 ng/mL) in both groups with NAT2 genotype‐adjusted doses, whereas the multidose parameters of valproate were not significantly affected neither by the selection of the NAT2 genotype (AUC0–48 h 2064 ± 455 vs. 1896 ± 185 μg h/mL; Cmax 96·4 ± 21·1 vs. 88·8 ± 7·2 μg/mL, for the fast and slow acetylators, respectively) nor the co‐administration of 83 or 182 mg of hydralazine.
What is new and conclusion
Comparable hydralazine exposures (differences in AUC0–inf of only 7%) were observed in this study with genetic selection of volunteers and concomitant dose adjustment. However, the conclusions have yet to be confirmed with a full‐powered 2 × 2 crossover study.
Hydralazine is extensively metabolized by the highly polymorphic N‐acetyltransferase 2, which complicates its correct dosing, and increases the costs of bioavailability or bioequivalence studies. We selected two groups of volunteers with genetically defined NAT2 activities and administered a single acetylator activity‐adjusted dose and achieved thereby comparable hydralazine exposures. Furthermore, the variability of key pharmacokinetic parameters was reduced, especially in the fast acetylator group.</description><identifier>ISSN: 0269-4727</identifier><identifier>EISSN: 1365-2710</identifier><identifier>DOI: 10.1111/jcpt.12155</identifier><identifier>PMID: 24702251</identifier><identifier>CODEN: JCPTED</identifier><language>eng</language><publisher>Oxford: Blackwell Publishing Ltd</publisher><subject>Acetylation ; acetylator ; Adult ; Antineoplastic agents ; Area Under Curve ; Arylamine N-Acetyltransferase - genetics ; bioavailability ; Biological and medical sciences ; Chromatography, High Pressure Liquid - methods ; Dose-Response Relationship, Drug ; Female ; General aspects ; Genotype ; Humans ; Hydralazine - administration & dosage ; Hydralazine - pharmacokinetics ; Male ; Medical sciences ; Mexico ; Middle Aged ; Pharmacology. Drug treatments ; phenotype ; Pilot Projects ; Polymorphism, Single Nucleotide ; Tablets ; Tandem Mass Spectrometry - methods ; Valproic Acid - administration & dosage ; Valproic Acid - pharmacokinetics ; Young Adult</subject><ispartof>Journal of clinical pharmacy and therapeutics, 2014-08, Vol.39 (4), p.368-375</ispartof><rights>2014 John Wiley & Sons Ltd</rights><rights>2015 INIST-CNRS</rights><rights>2014 John Wiley & Sons Ltd.</rights><rights>Copyright © 2014 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5645-762e2c91666f6552948a113c075a1d48b41b5c4e37e7e99469d19f0d933c93d3</citedby><cites>FETCH-LOGICAL-c5645-762e2c91666f6552948a113c075a1d48b41b5c4e37e7e99469d19f0d933c93d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjcpt.12155$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjcpt.12155$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28595143$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24702251$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Garcés-Eisele, S. J.</creatorcontrib><creatorcontrib>Cedillo-Carvallo, B.</creatorcontrib><creatorcontrib>Reyes-Núñez, V.</creatorcontrib><creatorcontrib>Estrada-Marín, L.</creatorcontrib><creatorcontrib>Vázquez-Pérez, R.</creatorcontrib><creatorcontrib>Juárez-Calderón, M.</creatorcontrib><creatorcontrib>Guzmán-García, M. O.</creatorcontrib><creatorcontrib>Dueñas-González, A.</creatorcontrib><creatorcontrib>Ruiz-Argüelles, A.</creatorcontrib><title>Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure</title><title>Journal of clinical pharmacy and therapeutics</title><addtitle>J Clin Pharm Ther</addtitle><description>Summary
What is known and objective
Hydralazine is an inhibitor of DNA methyltransferases, whereas valproate interferes with histone deacetylation. In combination, they show a marked synergism in reducing tumour growth as well as development of metastasis and inducing cell differentiation. Hydralazine is metabolized by the highly polymorphic N‐acetyltransferase 2. The current pilot study was performed to analyse the pharmacokinetic parameters of a single dose of hydralazine in 24 h (one tablet with 83 mg for slow acetylators and one tablet with 182 mg for fast acetylators) and three fixed doses of valproate (one tablet of controlled liberation with 700 mg every 8 h) in healthy genetically selected volunteers. Selection was performed based on their NAT2 activity as deduced from their genotype.
Methods
An open label non‐randomized single arm study was conducted in two groups of six healthy volunteers of both genders aged 20–45 years with a body mass index 22·2–26·9 which were classified as fast or slow acetylators after genotyping 3 SNPs that cover 99·9% of the NAT2 variants in the Mexican population. Blood samples were collected predose and serially post‐dose in an interval of 48 h. Hydralazine and valproate concentrations were determined by ultra‐high performance liquid chromatography (UPLC) coupled to tandem mass spectroscopy (MS/MS).
Results and discussion
The AUC0–48 h and Cmax of hydralazine were almost identical (1410 ± 560 vs. 1446 ± 509 ng h/mL and 93·4 ± 16·7 vs. 112·5 ± 42·1 ng/mL) in both groups with NAT2 genotype‐adjusted doses, whereas the multidose parameters of valproate were not significantly affected neither by the selection of the NAT2 genotype (AUC0–48 h 2064 ± 455 vs. 1896 ± 185 μg h/mL; Cmax 96·4 ± 21·1 vs. 88·8 ± 7·2 μg/mL, for the fast and slow acetylators, respectively) nor the co‐administration of 83 or 182 mg of hydralazine.
What is new and conclusion
Comparable hydralazine exposures (differences in AUC0–inf of only 7%) were observed in this study with genetic selection of volunteers and concomitant dose adjustment. However, the conclusions have yet to be confirmed with a full‐powered 2 × 2 crossover study.
Hydralazine is extensively metabolized by the highly polymorphic N‐acetyltransferase 2, which complicates its correct dosing, and increases the costs of bioavailability or bioequivalence studies. We selected two groups of volunteers with genetically defined NAT2 activities and administered a single acetylator activity‐adjusted dose and achieved thereby comparable hydralazine exposures. Furthermore, the variability of key pharmacokinetic parameters was reduced, especially in the fast acetylator group.</description><subject>Acetylation</subject><subject>acetylator</subject><subject>Adult</subject><subject>Antineoplastic agents</subject><subject>Area Under Curve</subject><subject>Arylamine N-Acetyltransferase - genetics</subject><subject>bioavailability</subject><subject>Biological and medical sciences</subject><subject>Chromatography, High Pressure Liquid - methods</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>General aspects</subject><subject>Genotype</subject><subject>Humans</subject><subject>Hydralazine - administration & dosage</subject><subject>Hydralazine - pharmacokinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mexico</subject><subject>Middle Aged</subject><subject>Pharmacology. Drug treatments</subject><subject>phenotype</subject><subject>Pilot Projects</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Tablets</subject><subject>Tandem Mass Spectrometry - methods</subject><subject>Valproic Acid - administration & dosage</subject><subject>Valproic Acid - pharmacokinetics</subject><subject>Young Adult</subject><issn>0269-4727</issn><issn>1365-2710</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqN0U9rFDEYBvAgit1WL34AGRBBhGnzP5tj2dpVKbWHBY8hm3kHZ80ka5Kp3X56Z9xtBQ9iLiHwe9-H8CD0iuBTMp6zjduWU0KJEE_QjDApaqoIfopmmEpdc0XVETrOeYMxloqy5-iIcoUpFWSG0hIClM5VGTy40sVQxba6jX4IBSDlyoamcjG42HfFhlI1MUNlm82QSw_j24NtclXiiPqtTXbtofq2a5L19r4LcHZr_TZFW6CCu23MQ4IX6FlrfYaXh_sErS4_rBYf66svy0-L86vaCclFrSQF6jSRUrZSCKr53BLCHFbCkobP15yshePAFCjQmkvdEN3iRjPmNGvYCXq3XzvG_xggF9N32YH3NkAcsiGCqzmX48r_ooIpSvRI3_xFN3FIYfzHpBjTWslp4fu9cinmnKA129T1Nu0MwWbqzEydmd-djfj1YeWw7qF5pA8ljeDtAdjsrG-TDa7Lf9xcaEH4lEr27mfnYfePSPN5cbN6CK_3M10ucPc4Y9N3IxVTwny9XprrG3lxgS_HB_sFuGW9hA</recordid><startdate>201408</startdate><enddate>201408</enddate><creator>Garcés-Eisele, S. J.</creator><creator>Cedillo-Carvallo, B.</creator><creator>Reyes-Núñez, V.</creator><creator>Estrada-Marín, L.</creator><creator>Vázquez-Pérez, R.</creator><creator>Juárez-Calderón, M.</creator><creator>Guzmán-García, M. O.</creator><creator>Dueñas-González, A.</creator><creator>Ruiz-Argüelles, A.</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><general>Hindawi Limited</general><scope>BSCLL</scope><scope>IQODW</scope><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>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>7X8</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>201408</creationdate><title>Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure</title><author>Garcés-Eisele, S. J. ; Cedillo-Carvallo, B. ; Reyes-Núñez, V. ; Estrada-Marín, L. ; Vázquez-Pérez, R. ; Juárez-Calderón, M. ; Guzmán-García, M. O. ; Dueñas-González, A. ; Ruiz-Argüelles, A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5645-762e2c91666f6552948a113c075a1d48b41b5c4e37e7e99469d19f0d933c93d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Acetylation</topic><topic>acetylator</topic><topic>Adult</topic><topic>Antineoplastic agents</topic><topic>Area Under Curve</topic><topic>Arylamine N-Acetyltransferase - genetics</topic><topic>bioavailability</topic><topic>Biological and medical sciences</topic><topic>Chromatography, High Pressure Liquid - methods</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>General aspects</topic><topic>Genotype</topic><topic>Humans</topic><topic>Hydralazine - administration & dosage</topic><topic>Hydralazine - pharmacokinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mexico</topic><topic>Middle Aged</topic><topic>Pharmacology. Drug treatments</topic><topic>phenotype</topic><topic>Pilot Projects</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Tablets</topic><topic>Tandem Mass Spectrometry - methods</topic><topic>Valproic Acid - administration & dosage</topic><topic>Valproic Acid - pharmacokinetics</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Garcés-Eisele, S. J.</creatorcontrib><creatorcontrib>Cedillo-Carvallo, B.</creatorcontrib><creatorcontrib>Reyes-Núñez, V.</creatorcontrib><creatorcontrib>Estrada-Marín, L.</creatorcontrib><creatorcontrib>Vázquez-Pérez, R.</creatorcontrib><creatorcontrib>Juárez-Calderón, M.</creatorcontrib><creatorcontrib>Guzmán-García, M. O.</creatorcontrib><creatorcontrib>Dueñas-González, A.</creatorcontrib><creatorcontrib>Ruiz-Argüelles, A.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Journal of clinical pharmacy and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Garcés-Eisele, S. J.</au><au>Cedillo-Carvallo, B.</au><au>Reyes-Núñez, V.</au><au>Estrada-Marín, L.</au><au>Vázquez-Pérez, R.</au><au>Juárez-Calderón, M.</au><au>Guzmán-García, M. O.</au><au>Dueñas-González, A.</au><au>Ruiz-Argüelles, A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure</atitle><jtitle>Journal of clinical pharmacy and therapeutics</jtitle><addtitle>J Clin Pharm Ther</addtitle><date>2014-08</date><risdate>2014</risdate><volume>39</volume><issue>4</issue><spage>368</spage><epage>375</epage><pages>368-375</pages><issn>0269-4727</issn><eissn>1365-2710</eissn><coden>JCPTED</coden><abstract>Summary
What is known and objective
Hydralazine is an inhibitor of DNA methyltransferases, whereas valproate interferes with histone deacetylation. In combination, they show a marked synergism in reducing tumour growth as well as development of metastasis and inducing cell differentiation. Hydralazine is metabolized by the highly polymorphic N‐acetyltransferase 2. The current pilot study was performed to analyse the pharmacokinetic parameters of a single dose of hydralazine in 24 h (one tablet with 83 mg for slow acetylators and one tablet with 182 mg for fast acetylators) and three fixed doses of valproate (one tablet of controlled liberation with 700 mg every 8 h) in healthy genetically selected volunteers. Selection was performed based on their NAT2 activity as deduced from their genotype.
Methods
An open label non‐randomized single arm study was conducted in two groups of six healthy volunteers of both genders aged 20–45 years with a body mass index 22·2–26·9 which were classified as fast or slow acetylators after genotyping 3 SNPs that cover 99·9% of the NAT2 variants in the Mexican population. Blood samples were collected predose and serially post‐dose in an interval of 48 h. Hydralazine and valproate concentrations were determined by ultra‐high performance liquid chromatography (UPLC) coupled to tandem mass spectroscopy (MS/MS).
Results and discussion
The AUC0–48 h and Cmax of hydralazine were almost identical (1410 ± 560 vs. 1446 ± 509 ng h/mL and 93·4 ± 16·7 vs. 112·5 ± 42·1 ng/mL) in both groups with NAT2 genotype‐adjusted doses, whereas the multidose parameters of valproate were not significantly affected neither by the selection of the NAT2 genotype (AUC0–48 h 2064 ± 455 vs. 1896 ± 185 μg h/mL; Cmax 96·4 ± 21·1 vs. 88·8 ± 7·2 μg/mL, for the fast and slow acetylators, respectively) nor the co‐administration of 83 or 182 mg of hydralazine.
What is new and conclusion
Comparable hydralazine exposures (differences in AUC0–inf of only 7%) were observed in this study with genetic selection of volunteers and concomitant dose adjustment. However, the conclusions have yet to be confirmed with a full‐powered 2 × 2 crossover study.
Hydralazine is extensively metabolized by the highly polymorphic N‐acetyltransferase 2, which complicates its correct dosing, and increases the costs of bioavailability or bioequivalence studies. We selected two groups of volunteers with genetically defined NAT2 activities and administered a single acetylator activity‐adjusted dose and achieved thereby comparable hydralazine exposures. Furthermore, the variability of key pharmacokinetic parameters was reduced, especially in the fast acetylator group.</abstract><cop>Oxford</cop><pub>Blackwell Publishing Ltd</pub><pmid>24702251</pmid><doi>10.1111/jcpt.12155</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0269-4727 |
| ispartof | Journal of clinical pharmacy and therapeutics, 2014-08, Vol.39 (4), p.368-375 |
| issn | 0269-4727 1365-2710 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1547846113 |
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| subjects | Acetylation acetylator Adult Antineoplastic agents Area Under Curve Arylamine N-Acetyltransferase - genetics bioavailability Biological and medical sciences Chromatography, High Pressure Liquid - methods Dose-Response Relationship, Drug Female General aspects Genotype Humans Hydralazine - administration & dosage Hydralazine - pharmacokinetics Male Medical sciences Mexico Middle Aged Pharmacology. Drug treatments phenotype Pilot Projects Polymorphism, Single Nucleotide Tablets Tandem Mass Spectrometry - methods Valproic Acid - administration & dosage Valproic Acid - pharmacokinetics Young Adult |
| title | Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure |
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