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PHARMACOGENOMICS |
From the Department of Laboratory Medicine, Daisan Hospital, Jikei University School of Medicine, Tokyo, Japan (Dr Ohnishi, Dr Akizuki), the Division of Gastroenterology & Hepatology, Daisan Hospital, Jikei University School of Medicine, Tokyo, Japan (Dr Murakami, Dr Mochizuki, Dr Takagi), and the Department of Pharmacotherapy, Meiji Pharmaceutical University, Tokyo, Japan (Dr Echizen).
Address for reprints: Akihiro Ohnishi, MD, PhD, Department of Laboratory Medicine, Daisan Hospital, Jikei University School of Medicine, 4-11-1 Izumihonchyo, Komae, Tokyo 201-8601.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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6ß-HC) in 31 CLD patients (9 with chronic hepatitis; 22 with cirrhosis comprising 20 Child-Pugh type A, 1 type B, and 1 type C) and 30 healthy subjects with different CYP2C19 genotypes. The mean (±SEM) omeprazole hydroxylation index in CLD patients with homozygous extensive metabolizer (EM) genotype (*1/*1, n = 8), heterozyous EM (*1/*2, n = 11; *1/*3, n = 6) genotypes and poor metabolizer (PM) genotypes (*2/*2, n = 3; *3/*3, n = 3) were 17.15 ± 2.12, 20.02 ± 2.63, and 26.04 ± 3.15, respectively, which were significantly higher compared with control subjects with the corresponding CYP2C19 genotypes (0.81 ± 0.09, 1.55 ± 0.20, and 15.5 ± 1.52). CLD patients with PM genotype had significantly (P < .05) higher omeprazole hydroxylation indexes than did those with homozygous EM genotype, and those with heterozygous EM genotypes had intermediate values. The mean CLcortisol6ß-HC decreased significantly (P < .001) in CLD patients compared with control subjects (1.19 ± 0.12 versus 2.26 ± 0.24 mL/min). Multiple regression analysis showed that CLD, serum albumin level, and CYP2C19 genotype correlated significantly (P < .05) with the omeprazole hydroxylation index, whereas no significant correlation was observed between CLcortisol6ß-HC and other variables, except CLD. Because CLD and genetic polymorphism of CYP2C19 act additively to reduce CYP2C19 activity, genotyping these patients may be of value in averting adverse reactions of drugs that depend on CYP2C19 for elimination.
Key Words: Chronic liver disease • cirrhosis • cytochrome P450 • CYP2C19 • CYP3A
Besides CLD, genetic polymorphism is another important covariate of CYP activity in certain isoforms.8 Because CYP2C19 is involved in the hepatic metabolism of many therapeutically important drugs, its metabolic activity is under control of genetic polymorphism. At present, as many as 15 variant isoforms have been reported and some of them (eg, CYP2C19*2 and CYP2C19*3 alleles) have been shown to be associated with defective enzyme function.9 Previous studies10,11 have shown that the possession of either the CYP2C19*2 or the CYP2C19*3 allele is associated with reduced in vivo CYP2C19 activity, depending on the gene dose; the CYP2C19 activity is lowest in the poor metabolizer (PM) genotypes (CYP2C19*2/*2, *2/*3, or *3/*3), followed by the heterozygous EM genotypes (CYP2C19*1/*2 or *1/*3) and then the homozygous EM genotype (CYP2C19*1/*1). Because the prevalence of defective alleles (CYP2C19*2 and *3) in Asians, including Japanese, is greater than that in whites,9,12,13 it is importance to study whether the genetic polymorphism of CYP2C19 would have an additive effect on the in vivo CYP2C19 activity, particularly in Japanese patients with CLD.
In this context, the aims of the present study were as follows: (1) to investigate the in vivo CYP2C19 activity in Japanese CLD patients with different CYP2C19 genotypes to assess the degree of interaction between CLD and genetic polymorphism on CYP2C19 activity, (2) to investigate which routine biochemical markers are clinically useful to predict CYP2C19 activity in CLD patients, and (3) to investigate the CLD-induced changes in CYP3A activity using the 3-hour partial formation clearance of cortisol to 6ß-hydroxycortisol (6ß-HC) as an in vivo CYP3A index.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Nine patients with chronic hepatitis (8 men and 1 woman) aged 52 to 84 years (mean ± SD, 66.0 ± 9.5 years) and weighing 40 to 74 kg (56.9 ± 10.2 kg), as well as 22 biopsy-proven cirrhotic patients (14 men and 8 women) aged 62 to 86 years (70.8 ± 6.1 years) and weighing 38 to 74 kg (55.1 ± 9.0 kg) were studied. The subjects were hospitalized at the Daisan Hospital of Jikei University School of Medicine. All patients were diagnosed as having chronic HCV infection by the detection of HCV-specific messenger RNA and antibody. One cirrhotic patient manifested ascites confirmed by abdominal ultrasonography and computed tomography. Five cirrhotic patients had endoscopy-confirmed esophageal varices. The severity of liver impairment (cirrhosis) was classified according to the Child-Pugh classification.14 Among the cirrhotic patients, 20 were graded as type A, 1 as type B, and 1 as type C. None had hepatic encephalopathy or had been treated with a transjugular intrahepatic portosystemic shunt15 Their clinical and biochemical data are summarized in Table I. They were normotensive and had no abnormalities in 12-lead electrocardiogram (ECG) recordings. All patients had been hospitalized for at least 2 weeks before the study and had no drugs or foods that might have inhibited or induced CYP activity.
Thirty healthy men, aged 25 to 67 years (50.6 ± 16.4 years) and weighing between 32 and 86 kg (61.5 ± 12.7 kg), participated in the study. All subjects were confirmed to be in good general health based on a complete physical examination, a standard 12-lead ECG, hemogram, and clinical laboratory tests. They had no known histories of allergic reactions to drugs or gastrointestinal, renal, hepatic, pulmonary, cardiac, or hematologic disease; they took no drugs or foods that might have an influence on CYP activity.
After fasting overnight, healthy subjects and patients with CLD received 20 mg omeprazole with 200 mL of water, and blood samples were withdrawn at 1.5 hours after dosing to determine plasma cortisol concentration and at 3 hours after dosing to determine plasma concentrations of omeprazole and 5-hydroxyomeprazole. In addition, 3-hour timed urine samples were collected. DNA samples were extracted from the buffy coat of blood samples, according to the standard protocol described below. All samples were numbered and handled anonymously to ensure the participants' privacy. All enrolled subjects and patients were asked to refrain from smoking during the entire study period.
Genotyping
Seven milliliters of peripheral blood was obtained, and DNA was extracted from peripheral leukocytes using a DNA extraction kit (IsoQuick, Micro Probe Co, Garden Grove, Calif). Genotyping analysis of the polymorphic CYP2C19 genes was performed according to the methods of de Morais et al12 and Kubota et al.13 The CYP2C19*2 and CYP2C19*3 alleles were detected by polymerase chain reaction methods using the following allele-specific primers: for identifying the CYP2C19*2 allele, the forward primer was 5'-AATTACAACCAGAGCTTGGC-3' and the reverse primer 5'-TATCACTTTCCATAAAAGCAAG-3'; for identifying the CYP2C19*3 allele, the forward primer was 5'-AACATCAGGATTGTAAGCAC-3', and the reverse primer was 5'-TCAGGGCTTGGTCAATATAG-3'. Amplified fragments were digested with endonuclease Msp I (25 units) for CYP2C19*2 and Bam HI (25 unit) for CYP2C19*3 followed by electrophoresis in 3% agarose gels.
Phenotypes of CYP2C19 were predicted based on the band patterns of the polymerase chain reaction products, according to the method of Kubota et al.13 Briefly, samples showing either CYP2C19*2 or CYP2C19*3 mutation in a homozygous state or CYP2C19*2 and CYP2C19*3 mutations in a combined heterozygous state were classified as the PM phenotype. Samples showing either CYP2C19*2 or CYP2C19*3 mutation in a heterozygous state were classified as the heterozygous EM phenotype, and those showing no CYP2C9*2 or CYP2C19*3 alleles were classified as the homozygous EM phenotype.9,10
Determination of Omeprazole and Its 5-Hydroxylated Metabolite in Plasma Samples
Omeprazole, the 5-hydroxy metabolite of omeprazole, and an internal standard [4,6-dimethyl-2-[(4-methoxy-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole] in plasma samples (500 µL) were extracted at pH 7.0 into ethyl acetate (1 mL).16 A portion of the extract (150 µL) was injected onto a normal-phase liquid chromatographic column (LiChrospher Diol, 5 µm, 120 x 4.0 mm, Merck, Germany). The mobile phase consisting of 0.05% ammonium hydroxide, 0.8% water, 8% methanol, and 55% isohexane in ethyl acetate was delivered at a flow rate of 1.0 mL/min. Retention times were 3.5, 8.0, and 5.5 minutes for omeprazole, the 5-hydroxyomeprazole, and the internal standard, respectively. The analytic compounds in the eluate were detected using a UV absorption method at 302 nm. The absolute recovery of omeprazole was greater than 90% at 25 to 2500 nmol/L, and that for 5-hydroxy metabolite was 70% at 50 to 3000 nmol/L. The limit of quantification for omeprazole and 5-hydroxyomeprazole were 25 and 50 nmol/L, respectively, with coefficients of variation (CV) of less than 20%.
Determination Plasma Cortisol and Urinary 6ß-Hydroxycortisol Levels
Urinary concentrations of unconjugated 6ß-HC were assayed with a high-performance liquid chromatography (HPLC) coupled with an ultraviolet (UV) absorption method according to that of Bienvenu et al, with minor modifications.17,18 Briefly, the mobile phase consisting of mixtures of acetonitrile/water/trichloroacetic acid (8/92/0.0005 vol/vol/wt, respectively) were adjusted to pH 2.5 by phosphoric acid and used in the assay. The HPLC system consisted of a reverse phase column (Prodigy 5µODS, 150 x 4.6 mm, Phenomenex, Torrance, Calif), a pump (L-7100, Hitachi Co Ltd, Tokyo, Japan), a UV detector (UV-8000, Tosoh Co Ltd, Tokyo, Japan) set at 244 nm, and a chromato-integrator (D-7500, Hitachi). The recovery rates for 6ß-HC, and the internal standards extracted from urine samples were greater than 95% with CV below 4%. Within-day and between-day CV for determining 200 and 20 ng/mL of urinary 6ß-HC and cortisol were both below 5%. Plasma cortisol concentrations were assayed using a fluorescence polarization immunoassay method (TDX system, Abbott Diagnostics, South Pasadena, Calif). Samples were prepared according to the manufacturer's instruction. Within-day and between-day CV for determining 0.05 and 0.1 µg/mL cortisol were both below 5%.
Pharmacokinetic and Statistical Analyses
Partial cortisol clearance to 6ß-HC (CLcortisol6ß-HC) was calculated as follows:
 | (Equation 1) |
Equation 1 is based on the assumption that the rate of 6ß-HC formation from cortisol equals the rate of appearance in urine and that 6ß-HC is eliminated in the urine without further metabolism. In addition, Equation 1 is based on the assumption that the midpoint plasma cortisol concentration represents the mean plasma cortisol concentration during the urine sampling period and that collection of urine is complete. Based on these assumptions, we consider that CLcortisol6ß-HC would represent the enzyme activity involved in the formation of 6ß-HC from cortisol. This parameter has been reported and assessed previously by our group using a potent CYP3A inhibitor, clarithromycin.18
Data are expressed as mean ± SEM throughout the study, unless otherwise stated. The mean values for the omeprazole hydroxylation index and CLcortisol6ß-HC between the CLD group and the control group as well as within the same group were compared statistically by multiple comparisons analysis followed by Dunnett's t test. Correlation between the above 2 indices of the in vivo metabolic activities of CYP2C19 and CYP3A and clinical characteristics and/or biochemical parameters was analyzed by multiple regression analysis (SAS version 8.2, SAS Institute, Cary, NC). A P value of <.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In healthy subjects with different CYP2C19 genotypes, the mean OPZ/5OH-OPZ ratio was significantly (P < .01) higher in subjects with the PM genotypes (15.5 ± 1.52) than in those with homozygous EM (0.81 ± 0.09) and heterozygous EM (1.55 ± 0.20) genotypes (Figure 1). In patients with CLD, the mean OPZ/5OH-OPZ ratio was significantly (P < .05) greater in patients with the PM genotypes (26.04 ± 3.15; n = 6) than in those with the homozygous EM genotype (17.15 ± 2.12; n =7), and the ratio in those with heterozygous EM genotypes (*1/*2, n = 11; *1/*3, n = 6; 20.02 ± 2.63) was in between the values of the 2 homozygous genotypes. The omeprazole hydroxylation index of patients with different CYP2C19 genotypes was significantly (P < .01) greater than that of control subjects with the corresponding genotypes.
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6ß-HC)6ß-HC obtained from CLD patients was significantly (P < .001) lower than that obtained from the control group (1.19 ±0.12 versus 2.26 ± 0.24 mL/min) (Figure 2). In patients with CLD, the mean CLcortisol6ß-HC decreased with an increase in severity of liver impairments as follows: 1.35 ± 0.26 in patients with chronic hepatitis and 1.12 ± 0.13 in patients with cirrhosis. The value was significantly lower (P < .05) in patients with cirrhosis compared with control subjects.
Correlations Between Omeprazole Hydroxylation Index or CLcortisol6ß-HC and Patients' Covariates
Table 2 shows the results of multiple regression analysis between the omeprazole hydroxylation index or CLcortisol6ß-HC and patients' covariates (ie, demographic parameters and laboratory tests) in CLD patients and control subjects. A significant (P < .05) correlation was observed between omeprazole hydroxylation index and disease condition, serum albumin level, or CYP2C19 genotype (Table 2). On the other hand, no significant correlation was observed between CLcortisol6ß-HC and all the variables tested, except disease condition (Table 2). There was a significant relationship between serum albumin concentration and the omeprazole hydroxylation index for overall data (n = 61, r = .526, P < .001) (Figure 3). When we analyzed the subset of CLD patients with the homozygous and heterozygous EM genotypes of CYP2C19 (ie, excluding control subjects and CLD patients with the PM genotype), the relation between serum albumin concentration and omeprazole hydroxylation index remained significant (n = 25, r = –.428, P < .05).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our data show a good agreement with the previous studies in patients with CLD1,2 that demonstrated a preferential reduction (77% from the baseline) of CYP2C19 activity assessed by the hydroxylation of mephenytoin compared with that of CYP3A4 (28%) and CYP2D6 (4%) assessed by hydroxylation of dapsone and debrisoquine, respectively. In the present study, the hydroxylation index of omeprazole in CLD patients with the homozygous EM genotype increased more than 10-fold than that of the healthy subjects with the same genotype, indicating a marked reduction in CYP2C19 activity associated with CLD. It is of note that the majority of our CLD patients had only mild liver dysfunction (9 had chronic hepatitis, and 20 of 22 cirrhotic patients were Child-Pugh type A), indicating that compared with other CYP isoforms (eg, CYP3A4), the hepatic CYP2C19 activity is more susceptible to CLD. This degree of reduction is in agreement with the report of Andersson et al.23 In contrast, the index of in vivo CYP3A activity, CLcortisol6ß-HC, obtained from CLD patients decreased to only a half of the control value. Kimura et al24 studied the omeprazole hydroxylation index in Japanese healthy subjects and patients with gastrointestinal disease and found that the hydroxylation indices obtained from 3 CLD patients with CYP2C19*1/*1 (n = 1) or CYP2C19*1/*2 (n = 2) were comparable with those observed in their healthy controls with the PM genotypes. Because they studied only 3 CLD patients under multiple dosing of the drug, they were unable to conclude whether their finding was attributable to a CLD-induced reduction of CYP2C19 activity or to partial saturation of the enzyme by multiple dosing. Our data confirm that the dramatic increase of the omeprazole hydroxylation index in CLD patients does represent a substantial reduction in the CYP2C19 activity in CLD patients. Nevertheless, the precise mechanism associated with the preferential reduction of this CYP isoform remains obscure at present.
We found that the omeprazole hydroxylation index obtained from CLD patients with the PM genotypes was further increased as compared with healthy subjects having the same genotype. Our data suggest that hepatic drug metabolizing enzyme(s) other than CYP2C19 may be involved in the in vivo 5-hydroxylation of omeprazole because both groups should have had no functional CYP2C19 enzyme. Our data are consistent with the study of Furuta et al,10 demonstrating that the area under the plasma concentrations (AUC) ratio of OPZ/5OH-OPZ in healthy subjects with PM genotypes coadministered the CYP3A4 inhibitor, clarithromycin, was 4 times greater than the value obtained from the same subjects given omeprazole alone. In the present study, we observed that the mean value of a putative index of CYP3A activity, CLcortisol6ß-HC, was approximately 50% lower in CLD patients than in control subjects. The data of Furuta et al10 and of our study collectively suggest that CYP3A4 may be involved in part in the 5-hydroxylation of omeprazole.
There are certain limitations in the present study. We assigned the phenotypes of CYP2C19 based solely on the genotyping of the 2 major mutations (CYP2C19*2 in exon 5 and CYP2C19*3 in exon 4). We did not genotype other rare variant alleles (eg, from CYP2C19*4 to CYP2C19*1225,26) that have been reported in non-Asian populations. However, because these 2 variant alleles have been shown to account for 98% of the PM phenotype in the Japanese population,6,7 we consider our assignment of the CYP2C19 phenotype to be valid. In addition, we evaluated the in vivo CYP2C19 activity based on the plasma omeprazole hydroxylation index at 3-hour postdose after a single oral load of 20 mg. Therefore, we cannot totally deny the possibility that an interindividual variability in the intestinal drug absorption may have jeopardized an accurate assessment of the enzyme activity. However, Andersson et al23 and Renetti et al27 reported that time required to reach peak plasma concentration of the drug was less than 3 hours after oral administration. We therefore consider that the 3-hour postdose hydroxylation index would be a robust in vivo index of CYP2C19 activity.
On the other hand, omeprazole is also known to be metabolized to omeprazole sulfone via CYP3A, and omeprazole sulfone is further metabolized to 5-hydroxyomeprazole sulfone via CYP2C19.28,29 In PMs of CYP2C19, the metabolic pathway of omeprazole to omeprazole sulfone is supposed to be enhanced, resulting in an accumulation of the sulfone metabolite. However, Ieiri et al22 have demonstrated that PM status does not elevate the omeprazole to omeprazole sulfone ratio (1.8 to 2.5–3; not significant) or change the AUC ratio (1.8 to 0.8–0.9) compared with the EM status. Their results suggest that the change in omeprazole hydroxylation index is mostly because of a change in CYP2C19 activity, with a minor contribution from CYP3A4, even in those with PM status. Because we did not measure the sulfone level, it remains unknown how liver damage modifies the metabolism of omeprazole in PMs and heterozygous EMs.
Many factors including gender,30,31 concomitant medication,24,28,29 age,32 liver disease,23,24,27 and length of the therapy33 have been reported to affect the in vivo metabolic activity of CYP2C19, thus confounding a simple relationship between genotypes and phenotypes. The multiple regression analysis performed in the present study revealed that age and gender were not associated with the reduction in in vivo CYP2C19 activity. However, caution has to be exercised in interpreting these results because the mean age of CLD patients was significantly higher than that of healthy controls (Table 1) and the relationship between age and CYP2C19 activity might not have been linear as assumed by the analysis. Several reports34-36 have demonstrated a significant correlation between the in vivo CYP2C19 activity and certain biochemical parameters associated with liver function (albumin, transaminase, and prothrombin index). The multiple regression analysis in the present study revealed that only serum albumin level, disease condition (ie, presence or absence of CLD), and genotype may explain the decrease of in vivo CYP2C19 activity.
We found that the mean CLcortisol6ß-HC obtained from CLD patients was decreased to 48% of that obtained from the healthy subjects. Because CYP3A isoforms (eg, CYP3A4 and CYP3A5) are primarily responsible for 6ß-hydroxylation of the endogenous cortisol, CLcortisol6ß-HC may be a clinically useful tool as an in vivo parameter of CYP3A activity. We have already reported that a 3-hour CLcortisol6ß-HC is a better clinical index of in vivo CYP3A activity than is the traditionally employed ratio of urinary 6ß-HC to cortisol for the assessment of the inhibitory effect of clarithromycin on CYP3A activity in patients receiving Helicobacter pylori eradication therapy.18 An oral administration of clarithromycin at 800 mg/d reduced CLcortisol6ß-HC to approximately 50% of the baseline value. The present finding that the mean CLcortisol6ß-HC of CLD patients was reduced by approximately 50% compared with healthy controls implies that the magnitude of reduction in in vivo CYP3A activity induced by CLD is largely comparable to that induced by clarithromycin. However, multiple regression analysis detected no significant correlation between CLcortisol6ß-HC and biochemical parameters associated with liver function. Thus, there is controversy of whether the 6ß-hydroxylation of cortisol is a reliable index of the in vivo hepatic CYP3A activity. It has been suggested that a certain amount of cortisol is secreted into the gut and is metabolized by the epithelial CYP3A on reabsorption. It is possible that CYP3A5 is expressed in the kidneys. Thus, the overall catalytic activity of cortisol 6ß-hydroxylation may be attributed not only to the hepatic CYP3A activity but also to certain extrahepatic tissues (eg, the kidney and the small intestine).37,38 This may be a reason we did not obtain any significant correlation between CLcortisol6ß-HC and the biochemical parameters of hepatic function. In addition, there is a concern that omeprazole administered to CLD patients and control subjects might have affected the CYP3A4 activity measured by CLcortisol6ß-HC. However, Furuta et al39 reported in their in vitro study performed with human liver microsomes that omeprazole is 50 times weaker as an inhibitor for CYP3A4 than for CYP2C19, and Tateishi et al40 demonstrated that omeprazole did not affect in vivo erythromycin breath test, an established index of CYP3A activity, in healthy subjects. In this context, we consider that the administration of omeprazole did not interfere with CLcortisol6ß-HC.
In conclusion, the present study demonstrated that the impaired CYP2C19 and CYP3A activity in CLD patients may be reflected by an increase in the omeprazole hydroxylation index and a decrease in CLcortisol6ß-HC, respectively. It is interesting that CLD appears to induce preferential reduction in CYP2C19 activity compared with CYP3A. The omeprazole hydroxylation index of CLD patients with the EM genotype of CYP2C19 was largely comparable to that of control subjects with the PM genotype. Further studies are required to assess whether the in vivo index of CYP2C19 may be useful for dosage adjustment of drugs that are eliminated mainly via CYP2C19-mediated hepatic metabolism.
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), squares (
), and triangles (
), respectively, and the healthy subjects having the corresponding CYP2C19 genotypes are denoted by open circles (
), squares (
), and triangles (
), respectively. The relationship between serum albumin level and hydroxylation index in CLD patients and healthy subjects is statistically significant (n = 61, r = –.526, P < .001, Y = 63.5 – 12.3X). OPZ/5OH-OPZ = plasma omeprazole to 5-hydroxyomeprazole concentration ratio.