Influence of CYP2C19 on the relationship between pharmacokinetics and intragastric pH of omeprazole administered by successive intravenous infusions in Chinese healthy volunteers.
OBJECTIVE
To explore the effect of cytochrome P450 2C19 (CYP2C19) polymorphisms on the relationship between the pharmacokinetics and pharmacodynamics of omeprazole administered by intravenous successive infusions in Chinese healthy volunteers.


METHODS
A total of 21 subjects [7 homozygous extensive metabolizers (homEMs), 9 heterozygous extensive metabolizers (hetEMs), 5 poor metabolizers (PMs)] received a 5-day course of omeprazole (40 mg) administered as a single dose daily during a 30-min period. Plasma concentrations were monitored by sampling at very short intervals for the first 8.5 h post-omeprazole administration and at 24 h post-administration, and intragastric pH was recorded on days 1 and 5.


RESULTS
After a single dose, both the area under the plasma concentration-time curve (AUC) and peak concentration (C(max)) were higher in PMs than in EMs. Both the mean half-life (t((1/2))) and total clearance in PMs were significantly higher and lower than those in homEMs and EMs, respectively. Mean AUC and C(max) ratios in homEMs, hetEMs, and PMs were 1.0:1.1:1.4 and 1.0:1.0:1.1, respectively. Relative to the values determined after a single dose in EMs, after repeated doses, the intragastric pH, AUC, C(max), and t((1/2)) had increased significantly, while the total clearance had decreased significantly. Mean AUC and C(max) ratios in homEMs, hetEMs, and PMs were 1.4:1.4:1.5 and 1.2:1.2:1.3, respectively, compared to those of a single dose. The mean intragastric pH was significantly higher in PMs than in EMs after the fifth dose.


CONCLUSIONS
There is a relationship between the pharmacokinetics and pharmacodynamics of omeprazole, with the latter depending in part on the duration of administration as evidenced by a higher AUC or C(max) and intragastric pH resulting from repeated dosing.
Wang
Yongqing
Y
Research Division of Clinical Pharmacology, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China. wangyq999@yahoo.com.cn
Zhang
Hongwen
H
Meng
Ling
L
Wang
Meifeng
M
Yuan
Hongyu
H
Ou
Ning
N
Zhang
Haibo
H
Li
Ziyan
Z
Shi
Ruihua
R
D000328:Adult; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002681:China; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D009853:Omeprazole / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values
D000897:Anti-Ulcer Agents; D054328:Proton Pump Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole