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Omeprazole as a CYP2C19 Marker in Chinese Subjects: Assessment of Its Gene-Dose Effect and Intrasubject Variability

From the School of Pharmacy (Dr. Yin, Dr. A. H. L. Chow, Dr. M. S. S. Chow), Department of Medicine and Therapeutics (Dr. Tomlinson), and Department of Biochemistry (Dr. Waye), Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

Address for reprints: Ophelia Q. P. Yin, PhD, School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Shatin, N.T., Hong Kong.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The objective of this study was to determine the reliability of omeprazole as a marker for CYP2C19 activity in Chinese subjects. In 27 healthy male Chinese subjects, the CYP2C19 phenotype was first determined with the standard mephenytoin hydroxylation index (HI) method. Subsequently, the subjects were randomized in a three-way crossover manner to receive an oral 40-mg dose from each of three omeprazole formulations (as part of a bioequivalence study). Multiple blood samples were obtained over 12 hours, and plasma concentrations of omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone were determined by a high-performance liquid chromatography (HPLC) method. Individual CYP2C19 genotype was determined by the polymerase chain reaction/restriction fragment length polymorphism method. To assess the specificity for CYP2C19 activity, the hydroxylation metabolic ratio (MR) of omeprazole (AUC_omeprazole/AUC_{5-hydroxyomeprazole}) was compared to mephenytoin HI and related to CYP2C19 genotype status. The inter- and intrasubject variabilities of MR were also calculated, and their magnitudes were compared. The intersubject MR varied more than 20 fold. Among the subjects, there was a gene-dose effect, and the mean MR was 1.76, 3.45, and 33.08, respectively, in the homozygous extensive metabolizers (wt/wt, n = 9), heterozygous extensive metabolizers (wt/m1 or wt/m2, n = 10), and poor metabolizers (m1/m1 or m1/m2, n = 7). However, the coefficients of variation for intrasubject MR only ranged from 4.5% to 33.7% over the three periods with the three formulations. The phenotype based on MR was concordant with HI. In view of the clear gene-dose effect, concordance with mephenytoin HI, and low intrasubject variability, omeprazole MR following a 40-mg oral dose can be considered as a specific and sensitive marker for CYP2C19 activity in Chinese subjects.

Key Words: Omeprazole • CYP2C19 • gene-dose effect

Mephenytoin has been extensively used as a marker for CYP2C19 activity. However, mephenytoin is not an ideal probe drug. It often causes sedation, especially in poor metabolizers or individuals with small body size.^12,13 The unavailability of mephenytoin in many parts of the world also limits its use for CYP2C19 phenotyping.

Omeprazole, a proton pump inhibitor, is much better tolerated than mephenytoin and has been proposed as an alternative probe drug for CYP2C19 activity.^14,15 Omeprazole is metabolized to two major metabolites, 5-hydroxyomeprazole and omeprazole sulfone. The formation of 5-hydroxyomeprazole is primarily mediated by CYP2C19, whereas the formation of omeprazole sulfone is catalyzed by CYP3A4 (Figure 1).^16,17 The hydroxylation pathway of omeprazole has been shown to cosegregate with S-mephenytoin hydroxylation in various populations, including Caucasians,^14,15,18 Japanese,¹⁹ and Korean²⁰ subjects. A gene-dose effect for omeprazole hydroxylation has also been shown in the previous studies in Caucasians¹⁶ and Japanese,^21,22 and this drug has been used as a CYP2C19 marker in various ethnic populations.^{14,15,18-20,23,24} There are, however, no valid data published for Chinese subjects. In addition, their reproducibility for CYP2C19 phenotyping (i.e., variability in CYP2C19 activity within an individual) is not clear. The purpose of this study is to assess the gene-dose effect and intrasubject variability of omeprazole hydroxylation as well as its relation with mephenytoin hydroxylation in Chinese subjects.

View larger version (13K): [in this window] [in a new window]   Figure 1. Metabolic pathway of omeprazole in humans.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
The study protocol was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. Written informed consent was obtained from each subject before participating in the study.

All subjects were nonsmokers and in good health based on medical history, physical examination, ECG evaluation, and routine laboratory tests (blood chemistry, hematology, and urine analysis). The subjects were not taking any prescription or nonprescription medication 2 weeks before and throughout the study. They were instructed to abstain from alcohol, grapefruit juice, and caffeine-containing beverages 48 hours before and during each study session.

Twenty-seven healthy male Hong Kong Chinese subjects ages 20 to 24 years, with weight between 54 and 71 kg, were selected. All subjects were phenotyped by a single oral 100-mg dose of racemic mephenytoin (Mesantoin®, Novartis, East Hanover, NJ) 2 months before the omeprazole study. An antimode of 1.0 in the log-mephenytoin hydroxylation index (HI), calculated as log₁₀ (µmol dose of S-mephenytoin/µmol 4'-hydroxy mephenytoin excreted in 8-h urine), was used to classify the extensive metabolizers (EMs) and poor metabolizers (PMs).²⁵

Omeprazole Pharmacokinetic Study
After completion of the phenotype determination and following a 2-month washout period, the subjects underwent a randomized three-way crossover study (over 3 weeks) for evaluation of bioavailability and intrasubject variability from three omeprazole formulations (as part of a bioequivalence study). After an overnight fast, the subjects received single 40-mg oral doses of omeprazole from each of the three formulations with 240 mL water: 2 x 20-mg Losec capsule (AstraZeneca), 2 x 20-mg MUPS (AstraZeneca), or 2 x 20-mg generic-formulation omeprazole capsule. Standardized meals were served 4 and 10 hours after dosing, and venous blood samples were collected at predose (0 h) and at 0.33, 0.67, 1.0, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours. Plasma was separated immediately by centrifugation and stored at -80°C until analysis.

Genotyping
To determine CYP2C19 genotype status, 10 mL blood was collected. The CYP2C19 wild-type (wt) gene and the two mutated alleles, CYP2C19_m1 and CYP2C19_m2, were identified by polymerase chain reaction (PCR) amplification with allele-specific primers as described by de Morais et al.^9,10 The PCR products were digested with Sma I and Bam HI restriction enzymes, respectively.

Determination of Omeprazole and Its Metabolites
Plasma concentrations of omeprazole and its two metabolites, 5-hydroxyomeprazole and omeprazole sulfone, were determined by a previously described high-performance liquid chromatography (HPLC) method,²⁶ with a slight modification: the HPLC system consisted of a Waters Alliance 2690 separation module, a Millennium³² chromatography management system, and a Waters 996 photodiode array detector (Waters Corporation, Milford, MA). The analytical column was a Waters Spherisorb ODS C₁₈ (5 µm, 250 mm x 4.6 mm), preceded with a Novo-Pak C₁₈ guard column (5 µm, 15 mm x 4.6 mm). A mixture of 0.02 M dihydrogen sodium phosphate buffer (pH 7.4) and acetonitrile (75:25, v/v) was used as the mobile phase, eluted at a flow rate of 1.0 mL/min. The eluate was monitored at a UV wavelength of 302 nm.

To each 0.5 mL of plasma sample, 200 µL of 2 mg/mL internal standard solution (phenacetin), 0.5 mL of 0.5 mol phosphate buffer (pH 8.0), and 5 mL of dichloromethane (with 10% acetonitrile) were added. The sample was mixed, followed by centrifugation at 2500 rpm for 20 minutes. The organic layer was transferred to a new tube and evaporated to dryness under a stream of nitrogen at room temperature. The residue was reconstituted with 200 µL of mobile phase, and 80 µL was injected for HPLC analysis.

The intra- and interday coefficients of variation for omeprazole and two metabolites were 0.7% to 11.8% and 2.6% to 13.0%, respectively. The accuracy of the assay ranged from 95.7% to 111.3%. The lower limit of detection for omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone was 10 ng/mL.

Pharmacokinetic Analysis
The plasma concentration data of omeprazole and its metabolites following the administration of each formulation were analyzed by a noncompartmental pharmacokinetic method,²⁷ with the aid of the WinNonlin program (version 2.1, Pharsight Corp.). Peak plasma concentrations (C_max) of omeprazole and its metabolites and the time to reach peak plasma concentrations (t_max) were obtained directly by inspection of the individual concentration-time data. Terminal elimination rate constant (_z) was estimated by linear regression of the terminal portion of the concentration-time curve, and the elimination half-life (t_1/2) was calculated as 0.693/_z. The area under the plasma concentration-time curve (AUC) was calculated using the trapezoidal rule and extrapolated to infinity. The apparent oral clearance (CL/F) of omeprazole was calculated as Dose/AUC.

The omeprazole hydroxylation metabolic ratio (MR), which is calculated as the ratio of AUCs of omeprazole t o 5-hydroxyomeprazole (AUC_omeprazole/AUC_{5-hydroxyomeprazole}),was used as an apparent marker for CYP2C19 activity.²⁸ (Although a single plasma ratio of omeprazole/5-hydroxyomeprazole is generally preferred for routine CYP2C19 phenotyping, the validity of such an approach in Chinese subjects has not been determined, and thus the plasma metabolic ratio based on the AUC values would be more accurate to initially establish its role as a marker for CYP2C19 activity.)

Statistical Analysis
Assessment of bioequivalence of the three formulations was based on the 90% confidence intervals for ln-transformed AUC and C_max ratios. Differences in the omeprazole hydroxylation MR among different formulations or different periods were assessed by analysis of variance (ANOVA).

The pharmacokinetic parameters of omeprazole and its metabolites among different genotype groups were compared using one-way ANOVA with Scheffe's multiple-comparison tests. Spearman's rank correlation coefficient (r_s) was used to assess the relationship between omeprazole MR values from each study period. A p-value of < 0.05 was considered statistically significant for all tests. All analyses were performed with the SPSS software (version 9.0, SPSS, Inc.).

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
No adverse effects related to omeprazole were observed throughout the study. One subject withdrew from the study, but this was not related to any adverse effects.

Among the 26 subjects analyzed (Table I), 9 were homozygous for the wild type in both exon 5 and exon 4 (wt/wt), 6 were heterozygous for the CYP2C19_m1 mutation (wt/m1), 4 were heterozygous for the CYP2C19_m2 mutation (wt/m2), 6 were homozygous for the CYP2C19_m1 mutation (m1/m1), and 1 was heterozygous for both CYP2C19_m1 and CYP2C19_m2 mutation (m1/m2). Thus, the subjects were classified into three genotype groups: homozygous EMs (wt/wt), heterozygous EMs (wt/m1 or wt/m2), and PMs (m1/m2 or m1/m1).

The three formulations were found to be bioequivalent, with 90% confidence intervals for the geometric mean ratio of C_max and AUC being well in the range of 80% to 125%, regardless of which formulation was used as reference. However, with each formulation, significant differences in omeprazole pharmacokinetics were observed among the three CYP2C19 genotype groups. Figure 2 and Table II show the representative relationship between different genotypes and the corresponding plasma concentrations of omeprazole or its metabolites following a single oral dose of 2 x 20-mg Losec capsules. Plasma concentrations of omeprazole and omeprazole sulfone were significantly higher, whereas 5-hydroxyomeprazole was significantly lower in PMs than in homozygous or heterozygous EMs. The AUC of omeprazole in PMs was 5.5- and 3.3-fold higher (both p < 0.001), and t_1/2 was 2.3- and 1.8-fold greater (both p < 0.001) in PMs compared to those in homozygous and heterozygous EMs, respectively. When comparing the two EM groups, the AUC of omeprazole was 1.7 times greater in heterozygous EMs than in homozygous EMs. The apparent oral clearance (CL/F) of omeprazole showed a ratio of 6.1:3.2:1.0 for the three genotype groups (homozygous EMs/heterozygous EMs/PMs).

View larger version (47K): [in this window] [in a new window]   Figure 2. Mean plasma concentration-time profiles of omeprazole (A), 5-hydroxyomeprazole (B), and omeprazole sulfone (C) after an oral administration of 40 mg omeprazole (in the form of 2 x 20-mg Losec capsules) in homozygous EMs (), heterozygous EMs (), and PMs () of CYP2C19.

Although the AUC of omeprazole sulfone in PMs was significantly greater than that in the homozygous and heterozygous EMs (7.6 and 3.7 times, both p < 0.001), there was no significant difference in the AUC ratios of omeprazole to omeprazole sulfone in each of the three genotype groups (Table II).

There were no significant differences in the mean omeprazole MR (represented by the ratio of AUC_omeprazole/AUC_{5-hydroxyomeprazole}) among the three formulations or three periods (p > 0.05, ANOVA). The intersubject variability of MR was, however, large. Following the single 40-mg dose (2 x 20-mg Losec capsules), omeprazole MR ranged from 0.68 to 53.99 among the study subjects and showed a clear gene-dose effect. The mean MR was 1.90, 3.05, and 31.19 in the homozygous EMs, heterozygous EMs, and PMs, respectively (Table II).

The individual MR values from each period were consistent, and all significantly correlated to each other (r_s = 0.89 for period 1 vs. 2, r_s = 0.87 for period 1 vs. 3, r_s = 0.93 for period 2 vs. 3, all p < 0.001). The mean MR and coefficient of variation (CV) values for individual subjects over the three periods are shown in Table III. The highest intraindividual CV observed was 33.7% (Table III).

As expected, the EM or PM phenotype designation for each subject based on omeprazole MR was concordant with that based on mephenytoin HI (Figure 3). The individual phenotype based on either mephenytoin HI or omeprazole MR was also consistent with the individual genotype (Table IV).

View larger version (8K): [in this window] [in a new window]   Figure 3. Concordance between omeprazole hydroxylation MR and log-mephenytoin HI (dashed line represents the cutoff value for CYP2C19 phenotype designation using log-mephenytoin HI). Homozygous EMs (), heterozygous EMs (), and PMs ().

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Our results show that there is a clear gene-dose effect based on the significant differences in the hydroxylation of omeprazole among the Chinese subjects with different CYP2C19 genotype status. In individuals who are homozygous EMs, heterozygous EMs, and PMs, their hydroxylation MR corresponds to 1.83, 3.27, and 32.24, respectively.

No significant differences in the AUC ratio of omeprazole to omeprazole sulfone were observed among the three different CYP2C19 genotype groups. This is not surprising since the sulfoxidation of omeprazole is primarily mediated by CYP3A4, whose activity would not be expected to differ among different CYP2C19 genotype groups. In PMs, the CYP2C19 activity is impaired, and the formation of omeprazole sulfone becomes the predominant pathway. Thus, the observed higher concentration of omeprazole sulfone in PMs can be attributed to the higher omeprazole concentration.

Although the EM or PM phenotype designation for each subject is consistent when using either the omeprazole MR or mephenytoin HI, the omeprazole MR seems to be better at distinguishing the subtle difference between homozygous and heterozygous EMs (Table IV). Thus, omeprazole may be more sensitive and robust in relating CYP2C19 phenotype to genotype.

The intrasubject variability of omeprazole MR ranged from 4.5% to 33.7% over the three study periods with the three formulations. This magnitude of variation is much less than the intersubject variation, which was more than 20-fold. Thus, our observed intrasubject variability is sufficiently narrow and indicates that intrasubject variability will not interfere with the separation of EMs from PMs based on the hydroxylation MR values. (In our study, the 95% confidence interval of omeprazole MR was 2.06-3.11 for EMs and 21.17-43.32 for PMs.)

While the gene-dose effect of omeprazole pharmacokinetics observed in our Chinese subjects is consistent with those reported in other populations such as Caucasians and Japanese,^16,21,22 our present study, also found that there are potential interethnic differences in CYP2C19 activity within a genotype (i.e., the homozygous EMs). When compared to the data published previously,²⁹ the mean clearance of omeprazole in the Hong Kong Chinese homozygous EMs is much lower than in Caucasian homozygous EMs (0.56 vs. 1.24 L/h/kg), whereas no significant difference is observed in the mean clearance between Hong Kong Chinese heterozygous EMs and the Caucasian heterozygous EMs (0.29 vs. 0.31 L/h/kg). This is consistent with the general observation by Ishizaki et al,³⁰ who found a lower clearance of omeprazole in Oriental EMs compared to Caucasian EMs. Such difference may be partly due to the interethnic differences in CYP2C19 activity within the homozygous EMs.

Our study results on the gene-dose effect of omeprazole pharmacokinetics may be clinically important. Since the reduction of acid secretion with omeprazole is related to the individual exposure of omeprazole (i.e., AUC of omeprazole), the PMs would be expected to have a higher peptic ulcer response rate if they take the same standard doses of omeprazole. This is supported by a recent study that demonstrates that the efficacy (eradication of Helicobacter pylori infection) of fixed-dose omeprazole 20 mg/day plus amoxicillin is 28.6%, 60%, and 100% in homozygous EMs, heterozygous EMs, and PMs of CYP2C19, respectively.²² This is likely to have further pharmacogenetic implications when treating different ethnic groups, as the prevalence of PMs differs in different populations.

Our study results on the intraindividual variability of CYP2C19 activity may be useful in designing future studies (e.g., in the determination of power and sample size for clinical investigations involving omeprazole as a CYP2C19 marker). In our study, the maximum intrasubject variability of omeprazole hydroxylation is 33.7%, and the mean variability is 18.2% in Chinese subjects. In white subjects, the variability was reported to be 2.7% to 38.8%.³¹ Knowing the intraindividual variability of specific ethnic groups can be helpful in improving the design of clinical studies involving such populations.

Although we found the omeprazole MR to be specific and sensitive and it can be used as a marker for CYP2C19 phenotype determination, one limitation of this study is that only male subjects were included. Based on the published literature, the effect of gender on CYP2C19 activity, however, is controversial,^32-34 and differences observed between the female and male subjects appear to be minor or insignificant. Another potential limitation is the inclusion of three formulations of omeprazole, which may theoretically contribute to the variability in the observed data in this study. However, the three formulations are bioequivalent, and our main data on hydroxylation MR are based on AUC_omeprazole/AUC_{5-hydroxyomeprazole} within each subject, which is unlikely to be influenced by the formulation effect.

In summary, based on its clear gene-dose effect, concordance with mephenytoin HI, and low intrasubject variability, omeprazole MR following a single 40-mg oral dose can be considered as a specific and sensitive marker for CYP2C19 phenotyping in Chinese subjects. Further work in a larger population, however, is needed to confirm this finding.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
This study was partially supported by grants from the Innovation and Technology Commission of the Government of Hong Kong SAR (ITS/174/00) and the Research Grants Council of Hong Kong SAR (CUHK4180/02M). We would like to thank Athena Hong, Sherry Lam, Katy Tsang, Rebecca Tsang, and Hillary Yiu for their valuable technical assistance in this investigation.

	FOOTNOTES

 
DOI: 10.1177/0091270004265702

Submitted for publication September 19, 2003; Revised version accepted March 22, 2004.

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