Estimation of CYP2C19 activity by the omeprazole hydroxylation index at a single point in time after intravenous and oral administration.
OBJECTIVE
The purpose of this study was to identify the common time point to achieve hydroxylation index (HI: omeprazole plasma concentration/5-hydroxyomeprazole plasma concentration) reflecting AUCOPZ/AUC5OH-OPZ after intravenous (IV) and oral (PO) administration.


METHODS
Twenty young and 28 elderly healthy subjects, including different CYP2C19 genotypes, were enrolled in the study. The young subjects received either 40 mg PO or 20 mg IV omeprazole, whereas the elderly subjects received 10 mg IV. The relation between AUCOPZ/AUC5OH-OPZ and HI was determined by Spearman's rank correlation. Multiple stepwise linear regression analysis was performed to identify the common time point to calculate HI that reflects AUCOPZ/AUC5OH-OPZ after IV.


RESULTS
In the correlation between HI and AUCOPZ/AUC5OH-OPZ IV at observed time points, HI3h showed the highest correlation coefficients (r = 0.894, p < 0.001) in all 48 subjects. The correlation of HI between IV and PO at observed time points showed that HI3h was highest (r = 0.916, p < 0.001) in 20 young subjects. Additionally, there was no significant difference between HI(3h) of IV and that of PO (12.9 +/- 15.9 and 12.9 +/- 15.1, p = 0.997). The regression equation of HI3h was the best to estimate AUCOPZ/AUC5OH-OPZ (AUCOPZ/AUC5OH-OPZ = 1.37 * HI3h + 0.18 * Age - 7.83, r2 = 0.883, p < 0.001).


CONCLUSIONS
This study demonstrated that HI3h after omeprazole IV was able to estimate AUCOPZ/AUC5OH-OPZ, as well as HI3h after PO. Additionally, CYP2C19 activity can be estimated more definitely by using HI after omeprazole IV without intestinal absorption.
Niioka
Takenori
T
Department of Pharmacy, Hirosaki University Hospital, Hirosaki, Japan.
Uno
Tsukasa
T
Sugimoto
Katsuyoshi
K
Sugawara
Kazunobu
K
Hayakari
Makoto
M
Tateishi
Tomonori
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D007275:Injections, Intravenous; D016014:Linear Models; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; C049963:5-hydroxymethylomeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole
Clin Pharmacol Ther. 2006 Jan;79(1):103-13
16413245
Arzneimittelforschung. 1991 Apr;41(4):420-2
1859516
Pharmacogenetics. 1997 Apr;7(2):115-9
9170148
Clin Pharmacokinet. 1996 Jul;31(1):9-28
8827397
Clin Pharmacol Ther. 1999 May;65(5):552-61
10340921
Clin Pharmacol Ther. 2003 Jun;73(6):517-28
12811361
Clin Pharmacokinet. 1991 Sep;21(3):195-212
1764870
Scand J Gastroenterol Suppl. 1985;108:113-20
3858973
J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Mar 7;832(2):241-8
16497565
Clin Pharmacokinet. 1992 Dec;23(6):469-76
1458764
Clin Pharmacokinet. 2005;44(11):1179-89
16231968
Clin Pharmacokinet. 2002;41(12 ):913-58
12222994
Clin Pharmacol Ther. 1996 Jun;59(6):647-53
8681489
Clin Pharmacol Ther. 2001 Nov;70(5):455-61
11719732
Br J Clin Pharmacol. 1999 Jan;47(1):115-9
10073749
Pharmacogenetics. 1995 Dec;5(6):358-63
8747407
Br J Clin Pharmacol. 1995 May;39(5):511-8
7669487
Clin Pharmacokinet. 1998 Nov;35(5):361-90
9839089
J Clin Pharmacol. 2005 Dec;45(12):1413-21
16291717
Pharmacogenetics. 1996 Dec;6(6):547-51
9014204
Br J Clin Pharmacol. 2004 Apr;57(4):487-94
15025747
Clin Pharmacol Ther. 1997 Aug;62(2):129-37
9284848
Aliment Pharmacol Ther. 1990 Jun;4(3):309-13
1983325
Clin Pharmacokinet. 1993 Jan;24(1):71-8
8448974
J Clin Pharmacol. 2005 Nov;45(11):1221-9
16239354
Eur J Clin Pharmacol. 2007 Feb;63(2):143-9
17203292
Pharmacogenomics. 2004 Mar;5(2):181-202
15016609
Mol Pharmacol. 1994 Oct;46(4):594-8
7969038
J Biol Chem. 1994 Jun 3;269(22):15419-22
8195181