Estimation of the area under the concentration-time curve of racemic lansoprazole by using limited plasma concentration of lansoprazole enantiomers.
OBJECTIVE
The purpose of this study was to identify the common time point that gives plasma concentrations of lansoprazole enantiomers that adequately reflect the AUC of racemic lansoprazole.


METHODS
A randomized, double-blind, placebo-controlled, crossover study in three phases was conducted at intervals of 2 weeks. Eighteen healthy Japanese volunteers, including three CYP2C19 genotype groups, took a single 60-mg oral dose of lansoprazole after 6 days of pretreatment, with either clarithromycin (800 mg/day), fluvoxamine (50 mg/day), or a placebo. Multiple linear regression analysis was used to identify the most informative sampling times of (R)- and (S)-lansoprazole, using one to three samples to estimate the AUC(0-infinity) of racemic lansoprazole.


RESULTS
The best R(2) in each prediction formula for the AUC of racemic lansoprazole using one, two, and three sampling points of (R)- and (S)-lansoprazole based on the data sets from all three pretreatment groups (n = 54) were 0.897, 0.930, and 0.929, respectively. The best prediction formula for the AUC of racemic lansoprazole, using the fewest sampling points of (R)- and (S)-lansoprazole, was AUC = 6.5 x C(3h) of (R)-lansoprazole + 13.7 x C(3h) of (S)-lansoprazole - 9,917.3 x G1 - 14,387.2 x G2 + 7,103.6 (P < 0.001), where C(3h) is the plasma concentration 3 h after administration, G1 = 1 for the homozygous extensive metabolizer (EM) and 0 for the other genotypes, G2 = 1 for the heterozygous EM and 0 for the other genotypes.


CONCLUSIONS
C(3h) monitoring of (R)- and (S)-lansoprazole is a useful time point to estimate the AUC of racemic lansoprazole. This method of plasma concentration monitoring at a few time points within 3 h might be more suitable for AUC estimation than CYP2C19 genotyping, particularly when lansoprazole is co-administered with CYP inhibitors.
Niioka
Takenori
T
Department of Pharmacy, Hirosaki University Hospital, Aomori, Japan.
Miura
Masatomo
M
Uno
Tsukasa
T
Yasui-Furukori
Norio
N
Hayakari
Makoto
M
Tateishi
Tomonori
T
Suzuki
Toshio
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017291:Clarithromycin / Q000494:pharmacology; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D064748:Dexlansoprazole; D004311:Double-Blind Method; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology; D005838:Genotype; D006207:Half-Life; D006801:Humans; D064747:Lansoprazole; D008297:Male; D008954:Models, Biological; D054328:Proton Pump Inhibitors / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D013237:Stereoisomerism
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D017291:Clarithromycin; D016666:Fluvoxamine; D064748:Dexlansoprazole