PMID- 20549497
OWN - NLM
STAT- MEDLINE
DCOM- 20101122
LR  - 20221207
IS  - 1432-1041 (Electronic)
IS  - 0031-6970 (Linking)
VI  - 66
IP  - 10
DP  - 2010 Oct
TI  - Influence of CYP2C19 genotype on the pharmacokinetics of R483, a CYP2C19 
      substrate, in healthy subjects and type 2 diabetes patients.
PG  - 1005-15
LID - 10.1007/s00228-010-0840-3 [doi]
AB  - OBJECTIVES: R483 is a thiazolidinedione peroxisome proliferator-activated 
      receptor gamma (PPARgamma) agonist with anti-diabetic properties and also a 
      cytochrome P450 2C19 (CYP2C19) substrate. The aim of the clinical studies 
      reported here was to investigate the influence of the CYP2C19 genotype on the 
      pharmacokinetics (PK) of R483 in healthy subjects and in type 2 diabetes mellitus 
      (T2DM) patients. METHODS: data came from two clinical studies, one including 58 
      Japanese and Caucasian healthy subjects and another including 93 Asian T2DM 
      patients. All subjects received multiple doses of R483, 20 mg once daily for the 
      healthy subjects and 12 mg once daily for the T2DM patients. Blood samples were 
      taken up to 24 h after the last dose to determine plasma concentrations of R483 
      and its major metabolites. RESULTS: poor metabolizers (PMs; CYP2C19*2/*2 or *2/*3 
      or *3/*3) had a higher plasma exposure and a lower clearance of the parent drug 
      than extensive metabolizers (EMs; CYP2C19*1/*1 or *1/*2 or *1/*3). The homozygous 
      PM/EM ratio for the area under the plasma concentration-time curve (AUC(0-24)) 
      [95% confidence interval] was 3.9 [2.7-5.7] for healthy subjects versus 2.0 
      [1.5-2.6] in T2DM patients. The heterozygous EMs were all T2DM patients, the 
      PM/EM ratio for AUC(0-24) was 1.5 [1.2-1.8]. The dose-normalized exposure to R483 
      was 1.2- (for PMs) and 2.4-fold (for EMs) higher in T2DM patients than in healthy 
      subjects. R483 was well tolerated in both studies. CONCLUSIONS: the plasma 
      exposure to R483 was significantly higher in PMs than in EMs. R483 exhibits 
      different PK in healthy subjects and T2DM patients, and the difference in 
      exposure between EM and PM was less pronounced in T2DM patients than in healthy 
      subjects. Factors such as diabetes condition and age may influence the metabolism 
      of R483. This knowledge allowed for a realistic dose recommendation for poor 
      metabolizer T2DM patients.
FAU - Bogman, Katrijn
AU  - Bogman K
AD  - F. Hoffmann-La Roche Ltd, Basel, Switzerland. katrijn.bogman@roche.com
FAU - Silkey, Mariabeth
AU  - Silkey M
FAU - Chan, Siew Pheng
AU  - Chan SP
FAU - Tomlinson, Brian
AU  - Tomlinson B
FAU - Weber, Cornelia
AU  - Weber C
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20100612
PL  - Germany
TA  - Eur J Clin Pharmacol
JT  - European journal of clinical pharmacology
JID - 1256165
RN  - 0 (5-((4-(2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy)benzo(2) 
      thiophen-7-yl)methyl)-thiazolidine-2,4-dione)
RN  - 0 (Blood Glucose)
RN  - 0 (Capsules)
RN  - 0 (Glycated Hemoglobin A)
RN  - 0 (Tablets)
RN  - 0 (Thiazolidinediones)
RN  - 0 (Thiophenes)
RN  - 0 (hemoglobin A1c protein, human)
RN  - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
RN  - EC 1.14.14.1 (CYP2C19 protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2C19)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Analysis of Variance
MH  - Area Under Curve
MH  - Aryl Hydrocarbon Hydroxylases/*genetics/metabolism
MH  - Asian People/*genetics
MH  - Biological Availability
MH  - Blood Glucose/metabolism
MH  - Capsules
MH  - Chromatography, Liquid
MH  - Cytochrome P-450 CYP2C19
MH  - Diabetes Mellitus, Type 2/*enzymology/genetics
MH  - Female
MH  - Genotype
MH  - Glycated Hemoglobin
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Reference Values
MH  - Tablets
MH  - Tandem Mass Spectrometry
MH  - Thiazolidinediones/administration & dosage/adverse 
      effects/blood/*pharmacokinetics
MH  - Thiophenes/administration & dosage/adverse effects/blood/*pharmacokinetics
MH  - Time Factors
MH  - White People/*genetics
EDAT- 2010/06/16 06:00
MHDA- 2010/12/14 06:00
CRDT- 2010/06/16 06:00
PHST- 2009/07/10 00:00 [received]
PHST- 2010/05/12 00:00 [accepted]
PHST- 2010/06/16 06:00 [entrez]
PHST- 2010/06/16 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
AID - 10.1007/s00228-010-0840-3 [doi]
PST - ppublish
SO  - Eur J Clin Pharmacol. 2010 Oct;66(10):1005-15. doi: 10.1007/s00228-010-0840-3. 
      Epub 2010 Jun 12.