The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid
This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA(90)) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identifie...
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| Veröffentlicht in: | European journal of clinical pharmacology 2007-07, Vol.63 (7), p.633-639 |
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| creator | DONALD, P. R PARKIN, D. P SEIFART, H. I SCHAAF, H. S VAN HELDEN, P. D WERELY, C. J SIRGEL, F. A VENTER, A MARITZ, J. S |
| description | This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA(90)) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10-12 mg/kg body weight.
INH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC(0-infinity)) and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC(0-infinity) and 2-h serum concentrations at which EBA(90) was reached.
EBA(90) was reached at an AUC(0-infinity) of 10.52 microg/ml per hour and 2-h serum concentrations of 2.19 microg/ml. An AUC(0-infinity) of 10.52 microg/ml per hour was reached by all 66 patients receiving a 10-12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 microg/ml was reached by all 66 patients receiving 10-12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators.
At a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC(0-infinity) and 2-h INH serum concentrations associated with EBA(90), as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH. |
| doi_str_mv | 10.1007/s00228-007-0305-5 |
| format | Article |
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INH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC(0-infinity)) and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC(0-infinity) and 2-h serum concentrations at which EBA(90) was reached.
EBA(90) was reached at an AUC(0-infinity) of 10.52 microg/ml per hour and 2-h serum concentrations of 2.19 microg/ml. An AUC(0-infinity) of 10.52 microg/ml per hour was reached by all 66 patients receiving a 10-12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 microg/ml was reached by all 66 patients receiving 10-12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators.
At a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC(0-infinity) and 2-h INH serum concentrations associated with EBA(90), as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH.</description><identifier>ISSN: 0031-6970</identifier><identifier>EISSN: 1432-1041</identifier><identifier>DOI: 10.1007/s00228-007-0305-5</identifier><identifier>PMID: 17505821</identifier><language>eng</language><publisher>Heidelberg: Springer</publisher><subject>Acetylation ; Adult ; Antibiotics ; Antitubercular Agents - administration & dosage ; Antitubercular Agents - metabolism ; Antitubercular Agents - pharmacokinetics ; Area Under Curve ; Arylamine N-Acetyltransferase - genetics ; Biological and medical sciences ; Drug dosages ; Enzymes ; Female ; Genotype ; Genotype & phenotype ; Humans ; Isoniazid - administration & dosage ; Isoniazid - metabolism ; Isoniazid - pharmacokinetics ; Male ; Medical sciences ; Mycobacterium tuberculosis - drug effects ; Pharmacology ; Pharmacology. Drug treatments ; Phenotype ; Time Factors ; Tuberculosis ; Tuberculosis, Pulmonary - drug therapy ; Tuberculosis, Pulmonary - metabolism ; Tuberculosis, Pulmonary - microbiology</subject><ispartof>European journal of clinical pharmacology, 2007-07, Vol.63 (7), p.633-639</ispartof><rights>2007 INIST-CNRS</rights><rights>Springer-Verlag 2007</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-d6ada249d2a8333c53737f32d0f28c6a5cd5ccfafb89330e391025eb0fc23f73</citedby><cites>FETCH-LOGICAL-c356t-d6ada249d2a8333c53737f32d0f28c6a5cd5ccfafb89330e391025eb0fc23f73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19025028$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17505821$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DONALD, P. R</creatorcontrib><creatorcontrib>PARKIN, D. P</creatorcontrib><creatorcontrib>SEIFART, H. I</creatorcontrib><creatorcontrib>SCHAAF, H. S</creatorcontrib><creatorcontrib>VAN HELDEN, P. D</creatorcontrib><creatorcontrib>WERELY, C. J</creatorcontrib><creatorcontrib>SIRGEL, F. A</creatorcontrib><creatorcontrib>VENTER, A</creatorcontrib><creatorcontrib>MARITZ, J. S</creatorcontrib><title>The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid</title><title>European journal of clinical pharmacology</title><addtitle>Eur J Clin Pharmacol</addtitle><description>This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA(90)) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10-12 mg/kg body weight.
INH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC(0-infinity)) and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC(0-infinity) and 2-h serum concentrations at which EBA(90) was reached.
EBA(90) was reached at an AUC(0-infinity) of 10.52 microg/ml per hour and 2-h serum concentrations of 2.19 microg/ml. An AUC(0-infinity) of 10.52 microg/ml per hour was reached by all 66 patients receiving a 10-12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 microg/ml was reached by all 66 patients receiving 10-12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators.
At a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC(0-infinity) and 2-h INH serum concentrations associated with EBA(90), as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH.</description><subject>Acetylation</subject><subject>Adult</subject><subject>Antibiotics</subject><subject>Antitubercular Agents - administration & dosage</subject><subject>Antitubercular Agents - metabolism</subject><subject>Antitubercular Agents - pharmacokinetics</subject><subject>Area Under Curve</subject><subject>Arylamine N-Acetyltransferase - genetics</subject><subject>Biological and medical sciences</subject><subject>Drug dosages</subject><subject>Enzymes</subject><subject>Female</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>Isoniazid - administration & dosage</subject><subject>Isoniazid - metabolism</subject><subject>Isoniazid - pharmacokinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>Pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenotype</subject><subject>Time Factors</subject><subject>Tuberculosis</subject><subject>Tuberculosis, Pulmonary - drug therapy</subject><subject>Tuberculosis, Pulmonary - metabolism</subject><subject>Tuberculosis, Pulmonary - microbiology</subject><issn>0031-6970</issn><issn>1432-1041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpFkM9u2zAMh4WhxZJ2e4BdBqNAgfagjRKt2D4GQbsVKLpL7gajP4u7RPIk55C-QF97CuwhJ1HExx-Jj7EvAr4JgOp7ApCy5rnkgKC4-sDmokTJBZTigs0BUPBFU8GMXaX0CiBUA_iRzUSlQNVSzNn7emuLzrvdwXpti-AKE5ItyJvihZO2w3E3RPLJ2UjJclncvSzX8r74bX0Yjv1I9tv_v-CLIQf2W4p70uFP5-3Q6TRRY9McPe1PzbysS8F39NaZT-zS0S7Zz9N7zdaPD-vVT_7868fTavnMNarFwM2CDMmyMZJqRNQKK6wcSgNO1npBShultSO3qRtEsNgIkMpuwGmJrsJrdjPG9jH8Pdg0tK_hEH3e2EpRlnUJjciQGCEdQ0rRuraP3Z7isRXQnsS3o_j2VJ7EtyrPfJ2CD5u9NeeJyXQGbieAkqady1J1l85ck-8EWeM_qPOMYg</recordid><startdate>20070701</startdate><enddate>20070701</enddate><creator>DONALD, P. 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S</creator><general>Springer</general><general>Springer Nature B.V</general><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>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20070701</creationdate><title>The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid</title><author>DONALD, P. R ; PARKIN, D. P ; SEIFART, H. I ; SCHAAF, H. S ; VAN HELDEN, P. D ; WERELY, C. J ; SIRGEL, F. A ; VENTER, A ; MARITZ, J. S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-d6ada249d2a8333c53737f32d0f28c6a5cd5ccfafb89330e391025eb0fc23f73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Acetylation</topic><topic>Adult</topic><topic>Antibiotics</topic><topic>Antitubercular Agents - administration & dosage</topic><topic>Antitubercular Agents - metabolism</topic><topic>Antitubercular Agents - pharmacokinetics</topic><topic>Area Under Curve</topic><topic>Arylamine N-Acetyltransferase - genetics</topic><topic>Biological and medical sciences</topic><topic>Drug dosages</topic><topic>Enzymes</topic><topic>Female</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Humans</topic><topic>Isoniazid - administration & dosage</topic><topic>Isoniazid - metabolism</topic><topic>Isoniazid - pharmacokinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mycobacterium tuberculosis - drug effects</topic><topic>Pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenotype</topic><topic>Time Factors</topic><topic>Tuberculosis</topic><topic>Tuberculosis, Pulmonary - drug therapy</topic><topic>Tuberculosis, Pulmonary - metabolism</topic><topic>Tuberculosis, Pulmonary - microbiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DONALD, P. R</creatorcontrib><creatorcontrib>PARKIN, D. P</creatorcontrib><creatorcontrib>SEIFART, H. I</creatorcontrib><creatorcontrib>SCHAAF, H. S</creatorcontrib><creatorcontrib>VAN HELDEN, P. D</creatorcontrib><creatorcontrib>WERELY, C. J</creatorcontrib><creatorcontrib>SIRGEL, F. A</creatorcontrib><creatorcontrib>VENTER, A</creatorcontrib><creatorcontrib>MARITZ, J. S</creatorcontrib><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>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>European journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>DONALD, P. R</au><au>PARKIN, D. P</au><au>SEIFART, H. I</au><au>SCHAAF, H. S</au><au>VAN HELDEN, P. D</au><au>WERELY, C. J</au><au>SIRGEL, F. A</au><au>VENTER, A</au><au>MARITZ, J. S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid</atitle><jtitle>European journal of clinical pharmacology</jtitle><addtitle>Eur J Clin Pharmacol</addtitle><date>2007-07-01</date><risdate>2007</risdate><volume>63</volume><issue>7</issue><spage>633</spage><epage>639</epage><pages>633-639</pages><issn>0031-6970</issn><eissn>1432-1041</eissn><abstract>This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA(90)) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10-12 mg/kg body weight.
INH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC(0-infinity)) and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC(0-infinity) and 2-h serum concentrations at which EBA(90) was reached.
EBA(90) was reached at an AUC(0-infinity) of 10.52 microg/ml per hour and 2-h serum concentrations of 2.19 microg/ml. An AUC(0-infinity) of 10.52 microg/ml per hour was reached by all 66 patients receiving a 10-12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 microg/ml was reached by all 66 patients receiving 10-12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators.
At a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC(0-infinity) and 2-h INH serum concentrations associated with EBA(90), as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH.</abstract><cop>Heidelberg</cop><cop>Berlin</cop><pub>Springer</pub><pmid>17505821</pmid><doi>10.1007/s00228-007-0305-5</doi><tpages>7</tpages></addata></record> |
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| subjects | Acetylation Adult Antibiotics Antitubercular Agents - administration & dosage Antitubercular Agents - metabolism Antitubercular Agents - pharmacokinetics Area Under Curve Arylamine N-Acetyltransferase - genetics Biological and medical sciences Drug dosages Enzymes Female Genotype Genotype & phenotype Humans Isoniazid - administration & dosage Isoniazid - metabolism Isoniazid - pharmacokinetics Male Medical sciences Mycobacterium tuberculosis - drug effects Pharmacology Pharmacology. Drug treatments Phenotype Time Factors Tuberculosis Tuberculosis, Pulmonary - drug therapy Tuberculosis, Pulmonary - metabolism Tuberculosis, Pulmonary - microbiology |
| title | The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid |
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