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PHARMACOGENETICS |
From the Clinical Pharmacology Research Center (Dr. Kim, Dr. Nafziger, Dr. Bertino), Department of Medicine (Dr. Nafziger, Dr. Bertino), Bassett Healthcare, Cooperstown, New York; Department of Pharmacology (Dr. Zhang, Dr. Sellers), Psychopharmacology and Dependence Research Unit (Dr. Sellers), Sunny Brook & Women's College, University of Toronto, Toronto, Ontario, Canada; and Section of Clinical Pharmacology and Experimental Therapeutics, The Children's Mercy Hospital, Kansas City, Missouri (Dr. Gaedigk). Originating Institution: Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, New York.
Address for reprints: Joseph S. Bertino Jr., PharmD, FCP, Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326-1394.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: CYP2C19 • dose dependency • omeprazole • intrasubject variability
Studies to date indicate that in adults, a single oral dose of omeprazole 20 to 40 mg can be used to measure the activity of CYP2C19 by quantitation of the ratio of omeprazole to 5'-hydroxyomeprazole 2 to 3 hours postdose.2,4-6 However, accurate quantitation of omeprazole and/or 5'-hydroxyomeprazole cannot always be determined with small single doses because of the resultant very low plasma concentrations in some individuals.3 In addition, the discrepancy observed in the activity of CYP2C19 in sex difference analysis may be related to administering different doses per body weight when a standard dose is used without considering the size of the subject's body frame.7 Weight-based higher doses (mg/kg of total body weight) may improve the quantitation of omeprazole and/or 5'-hydroxyomeprazole concentrations.
Determination of intraindividual variability is important when the pharmacokinetics of new drugs are being investigated. Inaccurate or false data may be obtained from a single pharmacokinetic study if a new drug is metabolized by an enzyme with large intraindividual variability. Appreciation of intrasubject variability due to changing enzyme activity is the rationale for the U.S. Food and Drug Administration's recommendation for replicate design studies for bioequivalence.
A single-center, open-label CYP2C19 phenotype study was conducted in 24 healthy Caucasian subjects. The objectives of our study were to determine the effects of sex and menstrual cycle phase on CYP2C19 activity, to evaluate intraindividual variability of omeprazole when it is used as a CYP2C19 probe, and to determine whether a reliable phenotype study can be conducted using weight-based omeprazole dosing. We have previously reported a lack of sex difference and menstrual cycle effects on the activity of CYP2C19 in the same study subjects, and these effects are described in an earlier report.8 We now report here the 3-month intraindividual variability in the activity of CYP2C19 as determined by omeprazole phenotyping. In addition, to improve assay quantitation of omeprazole and/or 5'-hydroxyomeprazole, we attempted to determine if dose dependency occurs with weight-based single doses of omeprazole.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Subjects
Healthy males and premenopausal females 
18 years of age who were not nursing or pregnant were eligible for the study. Caucasian subjects with a total body weight between 45 and 90 kg were enrolled. All participants underwent a complete history and physical examination, electrocardiogram, and blood chemistries prior to study participation. Females were required to use an acceptable nonhormonal method of birth control for the duration of the study. Exclusion criteria included serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal (AST 35 U/L, ALT 36 U/L); serum total bilirubin above 1.5 mg/dL; abnormal serum creatinine (normal range: 0.6-1.2 mg/dL in males, 0.5-1.0 mg/dL in females); inability to tolerate oral medication; a history of significant malabsorption; any chronic prescription or nonprescription medication, including oral and injectable contraceptives; concomitant therapy with drugs known to induce or inhibit the cytochrome P450 enzymes; use of tobacco products; and alcohol intake greater than 1 beer or the equivalent daily.
Menstrual Cycle Determination
Female subjects were instructed to keep a menstrual cycle diary and use a home diagnostic ovulation kit (Clear Plan Easy®, Unipath Research, Princeton, NJ) for 3 months prior to the study and throughout the study period. Day 1 of the menstrual cycle was defined by the onset of menstrual bleeding. Ovulation was confirmed during each cycle by testing first-morning urine for qualitative luteinizing hormone 3 days prior to the predicted mid-cycle and continued until a positive result was noted.
Phenotyping
Intraindividual Variability
Female subjects were phenotyped during the midfollicular and mid-luteal phases of their menstrual cycle for 3 complete cycles (visits 1-6). Male subjects were phenotyped once every 14 days for 12 weeks (visits 1-6). Subjects refrained from taking any medication, including nonprescription drugs, for at least 1 week before each study day. For female subjects of childbearing potential, urine pregnancy tests (Clear Blue Easy®, Unipath Research, Princeton, NJ) were performed and had to be negative prior to administration of omeprazole (Prilosec®, AstraZeneca, Wayne, Pa) on each study day. Under direct observation of an investigator, subjects with a body weight of 45 to 66 kg and 67 to 90 kg received a single oral dose of 30 mg and 40 mg omeprazole, respectively (weight-based dose of approximately 0.5 mg/kg). Dosing occurred between 06:00 and 09:00 hours after an 8-hour overnight fast. One venous blood sample (7 mL) was obtained by venipuncture 2 hours after the omeprazole dose, and subjects remained in the fasting state until after this venipuncture. The blood sample was collected in a heparinized tube and centrifuged for 15 minutes at 2800 rpm. Plasma samples were then stored at -80°C until analysis. A metabolic ratio of omeprazole to 5'-hydroxyomeprazole in the 2-hour sample was used for the phenotyping measure.
Weight-Based Dose Dependency of Omeprazole
Subjects with a body weight of 45 to 66 kg received one 40-mg oral dose of omeprazole (weight-based dose of approximately 0.65 mg/kg) after an 8-hour overnight fast during the fourth mid-follicular phase of the menstrual cycle for females and after a 2-week washout period from visit 6 for males. The sample collection to measure the metabolic ratio of omeprazole was carried out as previously described above.
Analytical Methods
Omeprazole and its metabolites, 5'-hydroxyomeprazole and omeprazole sulphone, were assayed in plasma with a modification of the method of Lagerstrom and Persson.9 The thawed plasma sample of 500 µL was transferred to 10-mL conical polypropylene tubes (Sarstedt, St. Laurent, Quebec), and 50 µLof10 µg/mL of H153 (internal standard) and 100 µL of phosphate buffer (pH 7.0) were added. The sample was then extracted with 4.5 mL of dichloromethane. It was centrifuged for 15 minutes at 3500 rpm after being horizontally shaken for 30 minutes. Next, the aqueous phase was aspirated, 3 mL of organic phase was transferred to a second set of tubes, and nitrogen at 45°C was used to evaporate to dryness. Then, 250 µL of mobile phase was added, and the solution was centrifuged for 5 minutes at 10,000 rpm. A 125-µL aliquot was injected into the high-performance liquid chromatography (HPLC) system with the wavelength of the UV detector set at 302 nm. The HPLC system consisted of a Hewlett-Packard 1050 isocratic pump, a 1050 autosampler, a 1050 UV detector, and a HP339611 integrator. A Spherisorb ODS2 (Hewlett-Packard, Waters, Mississauga, Ontario), 4.0 x 125 mm column, was used for the separation of omeprazole and its metabolites. The mobile phase used for elution consisted of 40 mM KH2PO4/CH3CN 74/26 vol/vol (pH 7.5), which delivered at a flow rate of 0.7 mL/min. The detection limits of the HPLC assay were 0.056 µM (omeprazole) and 0.028 µM (5'-hydroxyomeprazole). The intraday coefficients of variation of the assay at various concentrations were as follows: 5% (0.11 µM), 1% (1.1 µM), and 1% (5.5 µM) with omeprazole and 8% (0.11 µM), 2% (2.3 µM), and 3% (11 µM) with 5'-hydroxyomeprazole. The interday coefficients of variation were as follows: 1% (0.11 µM), 1% (1.1 µM), and 2% (5.5 µM) with omeprazole and 9% (0.11 µM), 1% (2.3 µM), and 2% (11 µM) with 5'-hydroxyomeprazole.
All subjects were genotyped for the presence of CYP2C19*1, *2, and *3 alleles. A single venous blood sample (7 mL) was collected into a Vacutainer® (Becton Dickson & Co., Franklin Lakes, NJ) tube with 1.5 mL of acid-citrate-dextrose solution A and stored at 4°C. Genomic DNA was prepared from whole blood with the QIAamp blood kit (Qiagen, Chatsworth, Calif). Genotype assays were adapted from Goldstein and Blaisdell.10
Statistical Analysis
Using interindividual variability data from published literature,11 the sample size needed to detect a 50% difference in omeprazole metabolic ratios, with an 
= 0.05 and a ß = 0.8, was 6. To allow for stratification by sex and body weight, 12 males and 12 premenopausal females were targeted for enrollment.
The metabolic ratios of omeprazole did not fit a normal distribution. Therefore, nonparametric testing was used where applicable. Mean (± SD) metabolic ratio and percent coefficient of variation (CV%) of 6 metabolic ratio measurements were determined for each subject. Median and interquartile ranges of CV% were determined to measure intraindividual variability in CYP2C19 activity. Median CV% of homozygous and heterozygous extensive metabolizers was compared using the Wilcoxon rank sum test. The sign test was used in subjects with body weights of 45 to 66 kg to determine weight-based dose dependency by comparing the median metabolic ratio of 6 visits (30-mg dose) with the metabolic ratio of visit 7 (40-mg dose). A p-value of 
0.05 was considered to be statistically significant. Data are presented as mean ± SD unless otherwise noted. All analyses were performed with SYSTAT Version 9 software (SYSTATTM, Evanston, Ill).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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One male subject had 2-hour omeprazole and its metabolite concentrations (5'-hydroxyomeprazole and omeprazole sulfone) below the detectable limits at visit 4. Because the administration of omeprazole was carried out under direct supervision of an investigator, noncompliance was ruled out. Absence of parent drug and its metabolites makes it likely that this blood sample was mishandled. Another explanation may be due to a late absorption of the drug with possible food intake, although subjects were instructed to fast. Therefore, this subject was excluded from the intraindividual variability analysis. Two male subjects were discontinued from the study after the second and third phenotyping visits for personal reasons, and they were excluded from the data analyses.
Intraindividual Variability
The metabolic ratios and the CV% of each subject are shown in Table II and Figures 1 and 2. Three male subjects with fewer than 6 phenotyping visits are excluded from the data analysis. The median CV% was 18.5% and ranged from 6.3% to 51.3%, with an interquartile range of 14.8% to 23.5%. The median CV% of the EMs with the CYP2C19*1/*1 genotype was 18.8% and ranged from 6.7% to 51.3%. The heterozygous EMs showed slightly lower CV% (median, 14.2%; range, 6.3%-23.5%), but the difference was not statistically significant (P = 0.31).
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Intraindividual variability was also evaluated, including the 3 male subjects with 2, 3, and 5 phenotyping visits. There was no difference in intraindividual variability. The median CV% was 18.8% and ranged from 2.5% to 51.3% with an interquartile range of 14.5% to 26.8%. The median CV% of the EMs with the CYP2C19*1/*1 genotype was 19.89% and ranged from 6.74% to 51.32%. The heterozygous EMs showed the median CV% of 10.24% (range, 2.50%-23.48%), and the difference was not statistically significant (P = .07).
Weight-Based Dose Dependency of Omeprazole
One male subject with a CYP2C19*1/*1 genotype was discontinued from the study after the second phenotyping visit. Therefore, only 11 subjects (5 males, 6 females) were included in the analysis of weight-based dose dependency. The mean metabolic ratios of each subject with 30 mg omeprazole (visits 1-6) and a single metabolic ratio measurement with 40 mg omeprazole (visit 7) are shown in Figure 3. The median metabolic ratios with 30 and 40 mg omeprazole were 0.94 and 1.27, respectively, and did not differ statistically (P = .75). The overall mean metabolic ratio was 1.31 ± 1.08 with 30 mg omeprazole and 1.50 ± 1.16 with 40 mg omeprazole.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Omeprazole is increasingly used as a phenotyping probe for CYP2C19. The metabolic ratio of the plasma concentration of omeprazole to a 5'-hydroxy metabolite after a single oral dose of omeprazole has been used as a measure of CYP2C19 activity.3,4 Omeprazole appears to have several characteristics of an ideal probe. It is safe and easy to administer, requires a single blood sample, uses a relatively uncomplicated chemical assay, and is specific for the CYP2C19 enzyme pathway.3,4 Thus, omeprazole is often the preferred pharmacologic probe in population phenotyping studies.3
Mephenytoin has been used as a probe for the polymorphic CYP2C19 enzyme. However, the possibility exists of an elevation in the urinary S/R-ratio, which is an artifact of hydrolysis of an acid-labile metabolite of mephenytoin.12,13 The mean percentage increases in the urinary S/R-ratio were determined to be 6.9% (range, 0%-104%), 20% (0%-139%), 177% (0%-2,600%), and 216% (0%-1100%) after 1, 3, 6, and 24 months at -20°C, respectively.13 In another study, the mean S/R-ratio increased by 22% and up to 85% in phenotypic EMs after both short-term (< 7 months) and prolonged (> 7 months) storage, respectively.14 In addition, mephenytoin has lost its clinical usefulness and may cause sedation, particularly in poor metabolizers (PMs) and small subjects.7,15,16 As noted below, mephenytoin has been used as a probe to assess intraindividual variability of CYP2C19, but the reader should be aware of the limitations of the use of this agent as a probe due to a hydrolysis of acid-labile metabolites.
Although separation of CYP2C19 EMs and PMs can reasonably be conducted between 2 and 4 hours after omeprazole intake,4,5 a high percentage of subjects have no detectable omeprazole or its metabolites in plasma.3,5 The possible explanations may be due to the delay of omeprazole absorption or gastric emptying,3 decreased absorption of the drug,17 presence of possible omeprazole ultra-extensive metabolizers, and decay of parent drug in storage.3 However, Balian et al3 found a decrease of only less than 1% in the concentration of omeprazole and an increase of less than 1% in the concentration of 5'-hydroxyomeprazole in the samples stored at -70°C over a 9-month period. In a study by Marinac et al,5 7% of African Americans had no detectable omeprazole in serum at 2 hours yet had measurable metabolite concentrations, 21% had 2-hour omeprazole and 5'-hydroxyomeprazole concentrations below detectable limits, and 2% had trace omeprazole concentrations but undetectable metabolite concentrations in all genotypic EMs. In addition, Balian et al3 have observed that 18.9% (18/95) of EMs had concentrations of omeprazole below the limit of detection at 2 hours postdose when 55.6% (10/18) of those ate within 1 hour of the test. Therefore, studies have concentrated on finding the optimal sampling time to minimize this problem. Marinac et al5 suggested that sampling times later than 2 hours postdose reflect concentration ratios of drug and metabolite that are less likely to be influenced by absorption of the parent drug and more likely to reflect primary metabolism. Chang et al4 reported that concentrations of omeprazole and metabolite obtained 3 or 4 hours after ingestion were ideal at distinguishing EM and PM phenotypes. However, our study, which involved a total of 148 phenotyping visits, shows that a sampling time at 2 hours postdose was adequate to measure concentrations of omeprazole and its metabolites, except in 1 phenotyping visit. Omeprazole and its metabolite concentrations (5'-hydroxyomeprazole and omeprazole sulfone) were below the detectable limits in 1 male subject (visit 4). Absence of parent drug and its metabolites makes it most likely that this blood sample was mishandled.
In our study, only the subjects with body weights between 45 and 66 kg received 30 mg (mean dose/body weight 0.45 mg/kg) and then 40 mg (mean 0.65 mg/kg) omeprazole to evaluate the dose dependency of omeprazole for CYP2C19 phenotype determination. The weight-based omeprazole dose was selected based on a study by Kovacs et al.7 In their multiple-dose study, 71.4% of the females who were homozygous or heterozygous extensive metabolizers had a metabolic ratio of omeprazole/5'-hydroxyomeprazole greater than 6, whereas only 20% of the males (heterozygous EMs) had a metabolic ratio greater than 6. Thus, they suggested that a higher weight-based dose in females (0.7 mg/kg) compared with a 0.5-mg/kg dose in males might account for the higher metabolic ratios in females.7 However, Kovacs et al did not specify whether female subjects were on oral contraceptives, which are known to be significant inhibitors of the CYP2C19 enzyme.18-20 Oral contraceptive use may explain the higher metabolic ratios that have been previously observed in females.21
A limited number of studies have determined intraindividual variability in the activity of CYP2C19. The metabolic ratio of omeprazole on 3 occasions over a 12-month period within EMs showed a wide range of variation (5.8%-64.3%) in 1 study.3 A mean variability of 18.2% (range, 2.7%-38.8%) was reported in Chinese male subjects who were EMs or PMs using 3 formulations of omeprazole over a 3-week period.22 Repeated determinations of the mephenytoin hydroxylation index (log10 [µmol S-mephenytoin given]/[µmol 4'-hydroxymephenytoin measured in urine]) showed a similar range of variability (5.4%-48.5%).3
We have observed similar intraindividual variability in the activity of CYP2C19. The metabolic ratios of omeprazole over a 3-month period showed a comparable range of variability (6.3%-51.3%), as seen in other studies. Although large intraindividual differences were observed in 21 subjects (16.3%) with a CV% of > 50% using mephenytoin as a probe drug,14 only 1 subject (4.8%) had a CV% > 50% in our study. In addition, the median CV% of 18.5% is considerably less than the variability of 28% measured by Taming et al,14 but their subjects were not genotyped, which may explain the greater variability in their study. Therefore, the metabolic ratio of omeprazole may be considered as a more reliable quantitative index of the CYP2C19 activity than the mephenytoin urinary S/R-ratio. As determined by others, prolonged storage of mephenytoin samples increases the S/R-ratio and may explain the differences in CYP2C19 intraindividual variability seen between mephenytoin and omeprazole.
Chang et al4 demonstrated a high correlation (rs = 0.85; P < .0001) of metabolic ratios of omeprazole when 17 Swedish subjects were phenotyped twice. They suggested that better reproducibility would have been found among EMs if several plasma samples had been used to calculate the AUC for omeprazole and its metabolites. Similar findings (rs = 0.97; P < .01) were reported in Bantu Tanzanians, who were phenotyped with 20 mg omeprazole 2 years apart.23
The CV% of homozygous and heterozygous EMs did not differ. However, it may be relevant to note that 3 subjects with a CV% greater than 30% were homozygous EMs. This is interesting given that 16.7% (3/18) of homozygous EMs had a CV% greater than 30%, whereas no heterozygous EMs showed such high variability. However, it should also be noted that the sample size was small (n = 3). In addition, the hypothesis should be investigated of whether a lower level of CYP2C19 protein in heterozygous individuals is the cause of variability. In a study by Yin et al,22 a similar variation was reported in homozygous EMs (mean, 19.3%; range, 4.5%-33.7%), heterozygous EMs (mean, 17.1%; range, 7.6%-26.1%), and PMs (mean, 18.5%; range, 9.5%-25.9%). Further investigation is warranted to determine whether homozygous and heterozygous subjects truly have a different extent of intraindividual variability.
One limitation of our study is that we did not address the potential dose dependency of a wider range of weight-based omeprazole doses. Because omeprazole inhibits its own metabolism and there is the possibility of saturable metabolism, evaluation of higher omeprazole doses could have addressed more relevant information of dose dependency. However, our study focused on the standard doses of omeprazole used in phenotyping studies, and our selection of omeprazole doses was based on the study by Kovacs et al.7
In conclusion, single doses of omeprazole for CYP2C19 phenotyping do not exhibit weight-based dose dependency when a dose of 0.45 to 0.65 mg/kg is used. Thus, higher doses of omeprazole may be used to improve the quantitation of omeprazole and/or 5'-hydroxyomeprazole concentrations in CYP2C19 phenotyping studies. Intraindividual variability data suggest fluctuations of 6.3% to 51.3% in the metabolic ratio of omeprazole for CYP2C19 activity. This within-individual variability should be taken into account when examining drugs metabolized predominately by the CYP2C19 enzyme.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication June 25, 2003; Revised version accepted July 7, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Birkett DJ, Andersson T, Miners JO. Assays of omeprazole metabolism as a substrate probe for human CYP isoforms. Meth Enzymol. 1996;272: 132-139.[Medline] [Order article via Infotrieve]
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3. Balian JD, Sukhova N, Harris JW, et al. The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Clin Pharmacol Ther. 1995;57: 662-669.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. ChangM, DahlML, TybringG, etal. Use of omeprazoleasaprobe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics. 1995;5: 358-363.[Web of Science][Medline] [Order article via Infotrieve]
5. Marinac JS, Balian JD, Foxworth JW, et al. Determination of CYP2C19 phenotype in black Americans with omeprazole: correlation with genotype. Clin Pharmacol Ther. 1996;60: 138-144.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Streetman DS, Bleakley JF, Kim JS, et al. Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail." Clin Pharmacol Ther. 2000;68: 375-383.[CrossRef][Medline] [Order article via Infotrieve]
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8. Kim MJ, Bertino JS Jr, Gaedigk A, et al. Effect of sex and menstrual cycle phase on cytochrome P450 2C19 activity with omeprazole used as a biomarker. Clin Pharmacol Ther. 2002;72: 192-199.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Lagerstrom PO, Persson BA. Determination of omeprazole and metabolites in plasma and urine by liquid chromatography. J Chrom. 1984;309: 347-356.
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11. Ieiri I, Kubota T, Urae A, et al. Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, in Japanese subjects. Clin Pharmacol Ther. 1996;59: 647-653.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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19. Laine K, Tybring G, Bertilsson L. No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin Pharmacol Ther. 2000;68: 151-159.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Tamminga WJ, Wemer J, Oosterhuis B, et al. CYP2D6 and CYP2C19 activity in a large population of Dutch health volunteers: indications for oral contraceptive-related gender differences. Eur J Clin Pharmacol. 1999;55: 177-184.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
21. Shelepova T, Nafziger AN, Victory J, et al. Effect of oral contraceptives on drug metabolizing enzymes as measured by the validated Cooperstown 5+1 cocktail. Clin Pharmacol Ther. 2003;73: 49.
22. Yin OQP, Tomlinson B, Chow AHL, et al. Omeprazole as a CYP2C19 marker in Chinese subjects: assessment of its gene-dose effect and intrasubject variability. J Clin Pharmacol. 2004;44: 582-589.
23. Herrlin K, Massele AY, Jande M, et al. Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype. Clin Pharmacol Ther. 1998;64: 391-401.[CrossRef][Web of Science][Medline]
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); subjects with CYP2C19*1/*1 genotype (
).