Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The only existing study of CYP2C19*17-associated alterations in drug pharmacokinetics was retrospective and compared probe drug metabolic ratios. The CYP2C19*17 allele had been associated with a two- and fourfold decrease in omeprazole and S/R-mephenytoin metabolic ratios.
WHAT THIS STUDY ADDS: This study characterized the single-dose pharmacokinetics of omeprazole, along with the 5-hydroxy and sulphone metabolites, in CYP2C19*17/*17 and CYP2C19*1/*1 subjects. The observed differences in omeprazole AUC(infinity) suggest that the CYP2C19*17 allele is an important explanatory factor behind individual cases of therapeutic failure. AIMS To investigate the influence of the CYP2C19*17 allele on the pharmacokinetics of omeprazole, a commonly used CYP2C19 probe drug, in healthy volunteers.
METHODS: In a single-dose pharmacokinetic study, 17 healthy White volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1 received an oral dose of 40 mg of omeprazole. Plasma was sampled for up to 10 h postdose, followed by quantification of omeprazole, 5-hydroxy omeprazole and omeprazole sulphone by high-performance liquid chromatography.
RESULTS: The mean omeprazole AUC(infinity) of 1973 h nmol l(-1) in CYP2C19*17/*17 subjects was 2.1-fold lower [95% confidence interval (CI) 1.1, 3.3] than in CYP2C19*1/*1 subjects (4151 h nmol l(-1), P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC(infinity) of 1083 h nmol l(-1), 3.1-fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l(-1), P = 0.03). A pronounced correlation (r(2) = 0.95, P < 0.0001) was seen in the intraindividual omeprazole AUC(infinity) and omeprazole sulphone AUC(infinity) values.
CONCLUSIONS: The pharmacokinetics of omeprazole and omeprazole sulphone differ significantly between homozygous CYP2C19*17 and CYP2C19*1 subjects. For clinically important drugs that are metabolized predominantly by CYP2C19, the CYP2C19*17 allele might be associated with subtherapeutic drug exposure.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2008 |
---|---|
Erschienen: |
2008 |
Enthalten in: |
Zur Gesamtaufnahme - volume:65 |
---|---|
Enthalten in: |
British journal of clinical pharmacology - 65(2008), 5 vom: 15. Mai, Seite 767-74 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Baldwin, R Michael [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 23.07.2008 Date Revised 20.10.2021 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1111/j.1365-2125.2008.03104.x |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM177804882 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM177804882 | ||
003 | DE-627 | ||
005 | 20231223151021.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231223s2008 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1111/j.1365-2125.2008.03104.x |2 doi | |
028 | 5 | 2 | |a pubmed24n0593.xml |
035 | |a (DE-627)NLM177804882 | ||
035 | |a (NLM)18294333 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Baldwin, R Michael |e verfasserin |4 aut | |
245 | 1 | 0 | |a Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers |
264 | 1 | |c 2008 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 23.07.2008 | ||
500 | |a Date Revised 20.10.2021 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The only existing study of CYP2C19*17-associated alterations in drug pharmacokinetics was retrospective and compared probe drug metabolic ratios. The CYP2C19*17 allele had been associated with a two- and fourfold decrease in omeprazole and S/R-mephenytoin metabolic ratios | ||
520 | |a WHAT THIS STUDY ADDS: This study characterized the single-dose pharmacokinetics of omeprazole, along with the 5-hydroxy and sulphone metabolites, in CYP2C19*17/*17 and CYP2C19*1/*1 subjects. The observed differences in omeprazole AUC(infinity) suggest that the CYP2C19*17 allele is an important explanatory factor behind individual cases of therapeutic failure. AIMS To investigate the influence of the CYP2C19*17 allele on the pharmacokinetics of omeprazole, a commonly used CYP2C19 probe drug, in healthy volunteers | ||
520 | |a METHODS: In a single-dose pharmacokinetic study, 17 healthy White volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1 received an oral dose of 40 mg of omeprazole. Plasma was sampled for up to 10 h postdose, followed by quantification of omeprazole, 5-hydroxy omeprazole and omeprazole sulphone by high-performance liquid chromatography | ||
520 | |a RESULTS: The mean omeprazole AUC(infinity) of 1973 h nmol l(-1) in CYP2C19*17/*17 subjects was 2.1-fold lower [95% confidence interval (CI) 1.1, 3.3] than in CYP2C19*1/*1 subjects (4151 h nmol l(-1), P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC(infinity) of 1083 h nmol l(-1), 3.1-fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l(-1), P = 0.03). A pronounced correlation (r(2) = 0.95, P < 0.0001) was seen in the intraindividual omeprazole AUC(infinity) and omeprazole sulphone AUC(infinity) values | ||
520 | |a CONCLUSIONS: The pharmacokinetics of omeprazole and omeprazole sulphone differ significantly between homozygous CYP2C19*17 and CYP2C19*1 subjects. For clinically important drugs that are metabolized predominantly by CYP2C19, the CYP2C19*17 allele might be associated with subtherapeutic drug exposure | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Randomized Controlled Trial | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 7 | |a Anti-Ulcer Agents |2 NLM | |
650 | 7 | |a Mixed Function Oxygenases |2 NLM | |
650 | 7 | |a EC 1.- |2 NLM | |
650 | 7 | |a Aryl Hydrocarbon Hydroxylases |2 NLM | |
650 | 7 | |a EC 1.14.14.1 |2 NLM | |
650 | 7 | |a CYP2C19 protein, human |2 NLM | |
650 | 7 | |a EC 1.14.14.1 |2 NLM | |
650 | 7 | |a Cytochrome P-450 CYP2C19 |2 NLM | |
650 | 7 | |a EC 1.14.14.1 |2 NLM | |
650 | 7 | |a Omeprazole |2 NLM | |
650 | 7 | |a KG60484QX9 |2 NLM | |
700 | 1 | |a Ohlsson, Staffan |e verfasserin |4 aut | |
700 | 1 | |a Pedersen, Rasmus Steen |e verfasserin |4 aut | |
700 | 1 | |a Mwinyi, Jessica |e verfasserin |4 aut | |
700 | 1 | |a Ingelman-Sundberg, Magnus |e verfasserin |4 aut | |
700 | 1 | |a Eliasson, Erik |e verfasserin |4 aut | |
700 | 1 | |a Bertilsson, Leif |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t British journal of clinical pharmacology |d 1974 |g 65(2008), 5 vom: 15. Mai, Seite 767-74 |w (DE-627)NLM000097799 |x 1365-2125 |7 nnns |
773 | 1 | 8 | |g volume:65 |g year:2008 |g number:5 |g day:15 |g month:05 |g pages:767-74 |
856 | 4 | 0 | |u http://dx.doi.org/10.1111/j.1365-2125.2008.03104.x |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 65 |j 2008 |e 5 |b 15 |c 05 |h 767-74 |