Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects

Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to alt...
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Autor*in:	Shaul, Chanan [verfasserIn] Blotnick, Simcha Muszkat, Mordechai Bialer, Meir Caraco, Yoseph

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2016

Schlagwörter:	Warfarin Variant Allele Warfarin Dose Oral Clearance CYP2C9 Genotype

Anmerkung:	© Springer International Publishing Switzerland 2016

Übergeordnetes Werk:	Enthalten in: Molecular diagnosis & therapy - [S.l.] : Springer International, 2006, 21(2016), 1 vom: 22. Nov., Seite 75-83
Übergeordnetes Werk:	volume:21 ; year:2016 ; number:1 ; day:22 ; month:11 ; pages:75-83

Links:	Volltext

DOI / URN:	10.1007/s40291-016-0247-7

Katalog-ID:	SPR036757292

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520			\|a Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Trial registration: Clinicaltrials.gov Identifier NCT00162474.
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allfields	10.1007/s40291-016-0247-7 doi (DE-627)SPR036757292 (SPR)s40291-016-0247-7-e DE-627 ger DE-627 rakwb eng Shaul, Chanan verfasserin aut Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Trial registration: Clinicaltrials.gov Identifier NCT00162474. Warfarin (dpeaa)DE-He213 Variant Allele (dpeaa)DE-He213 Warfarin Dose (dpeaa)DE-He213 Oral Clearance (dpeaa)DE-He213 CYP2C9 Genotype (dpeaa)DE-He213 Blotnick, Simcha aut Muszkat, Mordechai aut Bialer, Meir aut Caraco, Yoseph (orcid)0000-0002-7959-2517 aut Enthalten in Molecular diagnosis & therapy [S.l.] : Springer International, 2006 21(2016), 1 vom: 22. Nov., Seite 75-83 (DE-627)51122799X (DE-600)2232973-0 1179-2000 nnns volume:21 year:2016 number:1 day:22 month:11 pages:75-83 https://dx.doi.org/10.1007/s40291-016-0247-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 21 2016 1 22 11 75-83
spelling	10.1007/s40291-016-0247-7 doi (DE-627)SPR036757292 (SPR)s40291-016-0247-7-e DE-627 ger DE-627 rakwb eng Shaul, Chanan verfasserin aut Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Trial registration: Clinicaltrials.gov Identifier NCT00162474. Warfarin (dpeaa)DE-He213 Variant Allele (dpeaa)DE-He213 Warfarin Dose (dpeaa)DE-He213 Oral Clearance (dpeaa)DE-He213 CYP2C9 Genotype (dpeaa)DE-He213 Blotnick, Simcha aut Muszkat, Mordechai aut Bialer, Meir aut Caraco, Yoseph (orcid)0000-0002-7959-2517 aut Enthalten in Molecular diagnosis & therapy [S.l.] : Springer International, 2006 21(2016), 1 vom: 22. Nov., Seite 75-83 (DE-627)51122799X (DE-600)2232973-0 1179-2000 nnns volume:21 year:2016 number:1 day:22 month:11 pages:75-83 https://dx.doi.org/10.1007/s40291-016-0247-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 21 2016 1 22 11 75-83
allfields_unstemmed	10.1007/s40291-016-0247-7 doi (DE-627)SPR036757292 (SPR)s40291-016-0247-7-e DE-627 ger DE-627 rakwb eng Shaul, Chanan verfasserin aut Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Trial registration: Clinicaltrials.gov Identifier NCT00162474. Warfarin (dpeaa)DE-He213 Variant Allele (dpeaa)DE-He213 Warfarin Dose (dpeaa)DE-He213 Oral Clearance (dpeaa)DE-He213 CYP2C9 Genotype (dpeaa)DE-He213 Blotnick, Simcha aut Muszkat, Mordechai aut Bialer, Meir aut Caraco, Yoseph (orcid)0000-0002-7959-2517 aut Enthalten in Molecular diagnosis & therapy [S.l.] : Springer International, 2006 21(2016), 1 vom: 22. Nov., Seite 75-83 (DE-627)51122799X (DE-600)2232973-0 1179-2000 nnns volume:21 year:2016 number:1 day:22 month:11 pages:75-83 https://dx.doi.org/10.1007/s40291-016-0247-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 21 2016 1 22 11 75-83
allfieldsGer	10.1007/s40291-016-0247-7 doi (DE-627)SPR036757292 (SPR)s40291-016-0247-7-e DE-627 ger DE-627 rakwb eng Shaul, Chanan verfasserin aut Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Trial registration: Clinicaltrials.gov Identifier NCT00162474. Warfarin (dpeaa)DE-He213 Variant Allele (dpeaa)DE-He213 Warfarin Dose (dpeaa)DE-He213 Oral Clearance (dpeaa)DE-He213 CYP2C9 Genotype (dpeaa)DE-He213 Blotnick, Simcha aut Muszkat, Mordechai aut Bialer, Meir aut Caraco, Yoseph (orcid)0000-0002-7959-2517 aut Enthalten in Molecular diagnosis & therapy [S.l.] : Springer International, 2006 21(2016), 1 vom: 22. Nov., Seite 75-83 (DE-627)51122799X (DE-600)2232973-0 1179-2000 nnns volume:21 year:2016 number:1 day:22 month:11 pages:75-83 https://dx.doi.org/10.1007/s40291-016-0247-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 21 2016 1 22 11 75-83
allfieldsSound	10.1007/s40291-016-0247-7 doi (DE-627)SPR036757292 (SPR)s40291-016-0247-7-e DE-627 ger DE-627 rakwb eng Shaul, Chanan verfasserin aut Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Trial registration: Clinicaltrials.gov Identifier NCT00162474. Warfarin (dpeaa)DE-He213 Variant Allele (dpeaa)DE-He213 Warfarin Dose (dpeaa)DE-He213 Oral Clearance (dpeaa)DE-He213 CYP2C9 Genotype (dpeaa)DE-He213 Blotnick, Simcha aut Muszkat, Mordechai aut Bialer, Meir aut Caraco, Yoseph (orcid)0000-0002-7959-2517 aut Enthalten in Molecular diagnosis & therapy [S.l.] : Springer International, 2006 21(2016), 1 vom: 22. Nov., Seite 75-83 (DE-627)51122799X (DE-600)2232973-0 1179-2000 nnns volume:21 year:2016 number:1 day:22 month:11 pages:75-83 https://dx.doi.org/10.1007/s40291-016-0247-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_266 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 21 2016 1 22 11 75-83
language	English
source	Enthalten in Molecular diagnosis & therapy 21(2016), 1 vom: 22. Nov., Seite 75-83 volume:21 year:2016 number:1 day:22 month:11 pages:75-83
sourceStr	Enthalten in Molecular diagnosis & therapy 21(2016), 1 vom: 22. Nov., Seite 75-83 volume:21 year:2016 number:1 day:22 month:11 pages:75-83
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Warfarin Variant Allele Warfarin Dose Oral Clearance CYP2C9 Genotype
isfreeaccess_bool	false
container_title	Molecular diagnosis & therapy
authorswithroles_txt_mv	Shaul, Chanan @@aut@@ Blotnick, Simcha @@aut@@ Muszkat, Mordechai @@aut@@ Bialer, Meir @@aut@@ Caraco, Yoseph @@aut@@
publishDateDaySort_date	2016-11-22T00:00:00Z
hierarchy_top_id	51122799X
id	SPR036757292
language_de	englisch
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As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. 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author	Shaul, Chanan
spellingShingle	Shaul, Chanan misc Warfarin misc Variant Allele misc Warfarin Dose misc Oral Clearance misc CYP2C9 Genotype Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects
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topic_title	Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects Warfarin (dpeaa)DE-He213 Variant Allele (dpeaa)DE-He213 Warfarin Dose (dpeaa)DE-He213 Oral Clearance (dpeaa)DE-He213 CYP2C9 Genotype (dpeaa)DE-He213
topic	misc Warfarin misc Variant Allele misc Warfarin Dose misc Oral Clearance misc CYP2C9 Genotype
topic_unstemmed	misc Warfarin misc Variant Allele misc Warfarin Dose misc Oral Clearance misc CYP2C9 Genotype
topic_browse	misc Warfarin misc Variant Allele misc Warfarin Dose misc Oral Clearance misc CYP2C9 Genotype
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title	Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects
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title_full	Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects
author_sort	Shaul, Chanan
journal	Molecular diagnosis & therapy
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author_browse	Shaul, Chanan Blotnick, Simcha Muszkat, Mordechai Bialer, Meir Caraco, Yoseph
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doi_str_mv	10.1007/s40291-016-0247-7
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title_sort	quantitative assessment of cyp2c9 genetic polymorphisms effect on the oral clearance of s-warfarin in healthy subjects
title_auth	Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects
abstract	Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Trial registration: Clinicaltrials.gov Identifier NCT00162474. © Springer International Publishing Switzerland 2016
abstractGer	Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Trial registration: Clinicaltrials.gov Identifier NCT00162474. © Springer International Publishing Switzerland 2016
abstract_unstemmed	Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Trial registration: Clinicaltrials.gov Identifier NCT00162474. © Springer International Publishing Switzerland 2016
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title_short	Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects
url	https://dx.doi.org/10.1007/s40291-016-0247-7
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author2	Blotnick, Simcha Muszkat, Mordechai Bialer, Meir Caraco, Yoseph
author2Str	Blotnick, Simcha Muszkat, Mordechai Bialer, Meir Caraco, Yoseph
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doi_str	10.1007/s40291-016-0247-7
up_date	2024-07-03T19:28:08.558Z
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fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR036757292</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519215912.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s2016 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s40291-016-0247-7</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR036757292</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s40291-016-0247-7-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Shaul, Chanan</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2016</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© Springer International Publishing Switzerland 2016</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. Objective The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance ($ CL_{S} $) among healthy subjects carrying different CYP2C9 genotypes. Methods Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Results Compared with carriers of the wild-type CYP2C91/1 genotype (n = 69), $ CL_{S} $ was reduced by 25, 39 and 47% among heterozygote for CYP2C92 (n = 41) CYP2C93 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). Conclusions The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. 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Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects

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