<i>In Vivo</i> Metabolic Activity of CYP2C19 and CYP3A in Relation to CYP2C19 Genetic Polymorphism in Chronic Liver Disease

Ohnishi, Akihiro; Murakami, S; Akizuki, Setsuko; Mochizuki, Junko; Echizen, Hirotoshi; Takagi, Ichiro

doi:10.1177/0091270005280787

Cited by 42 publications

(25 citation statements)

References 34 publications

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“…Ohnishi et al. 6 classified 31 patients with chronic liver diseases including chronic hepatitis and liver cirrhosis, and 30 healthy volunteers in terms of their CYP2C19 genotype and detected CYP2C19 activity with the omeprazole probe. They found that CYP2C19 activity in patients with chronic liver disease was significantly lower than that in healthy controls regardless of PM or EM.…”

Section: Discussionmentioning

confidence: 99%

Blood concentration of pantoprazole sodium is significantly high in hepatogenic peptic ulcer patients, especially those with a poor CYP2C19 metabolism

Shao

Jiang

et al. 2009

J of Digest Diseases

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OBJECTIVE: To determine the plasma concentration of pantoprazole sodium by high performance liquid chromatography and its distribution in patients with different CYP2C19 genotypes in an attempt to provide experimental data for the clinical dosage adjustment of the drug. METHODS: Patients with liver disease and associated peptic ulcer were genotyped according to their CYP2C19 wild‐type sequences and mutations in CYP2C19m1 and CYP2C19m2 by the principles of the American Surgical Association using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). The plasma concentration of pantoprazole sodium was detected after oral administration of the enteric‐coated capsules in all patients. Included in the present study were 21 patients with primary liver cancer complicated by pathogenic peptic ulcers (confirmed by endoscopy), 22 patients with fatty liver and 25 healthy volunteers between January 2006 and October 2007. The subjects were administered orally with pantoprazole sodium at 40 mg/day for 1 week consecutively. The drug concentration was detected at 24 h and 1 week after drug administration by drawing 3.0 mL blood from the cubital vein. RESULTS: The plasma concentration of pantoprazole sodium was related to the CYP2C19 enzyme type. The plasma concentration of extensive metabolizers (EM) was lower than that of poor metabolizers (PM) in the healthy control group at day 7 of drug administration. Regardless of PM or EM, the plasma concentration of pantoprazole sodium in primary liver cancer patients was higher than that in fatty liver patients, and even higher than that in healthy controls (P < 0.05). CONCLUSION: These results suggest that CYP2C19 activity is inversely correlated with the severity of liver disease, especially in PM patients.

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Section: Discussionmentioning

confidence: 99%

Blood concentration of pantoprazole sodium is significantly high in hepatogenic peptic ulcer patients, especially those with a poor CYP2C19 metabolism

Shao

Jiang

et al. 2009

J of Digest Diseases

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“…CYP2C19 has been identified as one of the more sensitive P450s to the presence of liver diseases such as hepatocellular carcinoma, hepatitis C, and chronic hepatitis and cirrhosis (Ohnishi et al, 2005;Frye et al, 2006). In addition, it has also been shown to be affected earlier than the other important drug-metabolizing P450s (Villeneuve and Pichette, 2004).…”

Section: Fisher Et Almentioning

confidence: 99%

Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

et al. 2009

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ABSTRACT:Members of the cytochrome P450 (P450) enzyme families CYP1, CYP2, and CYP3 are responsible for the metabolism of approximately 75% of all clinically relevant drugs. With the increased prevalence of nonalcoholic fatty liver disease (NAFLD), it is likely that patients with this disease represent an emerging population at significant risk for alterations in these important drug-metabolizing enzymes. The purpose of this study was to determine whether three progressive stages of human NALFD alter hepatic P450 expression and activity. Microsomes isolated from human liver samples diagnosed as normal, n ‫؍‬ 20; steatosis, n ‫؍‬ 11; nonalcoholic steatohepatitis (NASH) (fatty liver), n ‫؍‬ 10; and NASH (no longer fatty), n ‫؍‬ 11 were analyzed for P450 mRNA, protein, and enzyme activity. Microsomal CYP1A2, CYP2D6, and CYP2E1 mRNA levels were decreased with NAFLD progression, whereas CYP2A6, CYP2B6, and CYP2C9 mRNA expression increased. Microsomal protein expression of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 tended to decrease with NAFLD progression. Likewise, functional activity assays revealed decreasing trends in CYP1A2 (p ‫؍‬ 0.001) and CYP2C19 (p ‫؍‬ 0.05) enzymatic activity with increasing NAFLD severity. In contrast, activity of CYP2A6 (p ‫؍‬ 0.001) and CYP2C9 (diclofenac, p ‫؍‬ 0.0001; tolbutamide, p ‫؍‬ 0.004) was significantly increased with NAFLD progression. Increased expression of proinflammatory cytokines tumor necrosis factor ␣ and interleukin 1␤ was observed and may be responsible for observed decreases in respective P450 activity. Furthermore, elevated CYP2C9 activity during NAFLD progression correlated with elevated hypoxia-induced factor 1␣ expression in the later stages of NAFLD. These results suggest that significant and novel changes occur in hepatic P450 activity during progressive stages of NAFLD.

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“…Clinical studies confirm that the urinary metabolic ratio of caffeine, mephenytoin, debrisoquine, and chlorzoxazone, which are in vivo probes of CYP1A2, 2C9, 2D6, and 2E1, respectively, is reduced (Ohnishi et al, 2005;Frye et al, 2006). However, there is a paucity of data on the effect of cirrhosis on expression and activity of hepatic drug transporters (Ogasawara et al, 2010;More et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics

Wang

Collins

Kelly

et al. 2016

Drug Metabolism and Disposition

104

137

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In Vivo Metabolic Activity of CYP2C19 and CYP3A in Relation to CYP2C19 Genetic Polymorphism in Chronic Liver Disease

Cited by 42 publications

References 34 publications

Blood concentration of pantoprazole sodium is significantly high in hepatogenic peptic ulcer patients, especially those with a poor CYP2C19 metabolism

Blood concentration of pantoprazole sodium is significantly high in hepatogenic peptic ulcer patients, especially those with a poor CYP2C19 metabolism

Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease

Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics

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