Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently reported that disease-specific differential alterations in the hepatic expression of xenobiotic-metabolizing cytochrome P450 (CYP P450) enzymes occur in patients with advanced liver disease. In order to determine whether the observed changes in CYP proteins are modulated at pre- or post-translational levels, we have now examined the hepatic levels of mRNA for CYPs 1A2, 2C9, 2E1 and 3A4 by solution hybridization in the same livers of 20 controls (surgical waste from histologically normal livers), 32 cases of hepatocellular and 18 of cholestatic severe chronic liver disease. CYP1A2 mRNA and CYP1A immunoreactive protein were both reduced in livers with hepatocellular and cholestatic types of cirrhosis. In contrast, CYP3A4 mRNA and protein were reduced only in livers from patients with hepatocellular diseases. For 1A2 and 3A4 there were significant correlations between mRNA species and the respective protein contents (rS1A2 = 0.74, rS3A4 = 0.64, P < 0.0001). CYP2C9 mRNA was reduced in patients with both cholestatic and hepatocellular types of liver disease, but 2C protein was reduced only in patients with cholestatic dysfunction. The correlation between CYP2C9 mRNA and protein, was also significant (rs = 0.36, P < 0.005) but mRNA levels accounted for only 13% of the variability in protein rankings. This is probably a consequence of other CYP2C proteins apart from 2C9 being detected by the anti-2C antibody. CYP2E1 mRNA and protein were reduced in patients with cholestatic liver disease, but in hepatocellular disease the expression of only CYP2E1 mRNA was decreased. CYP2E1 mRNA was significantly correlated with CYP2E1 protein but accounted for only 18% of the variability in protein rankings (rs = 0.43, P < 0.0005). Taken collectively these data indicate that the disease-specific alterations of xenobiotic-metabolizing CYP enzymes among patients with cirrhosis is due, at least in part, to pre-translational mechanisms. The lack of a strong correlation between CYP2E1 mRNA and protein suggests that this gene, like its rat orthologue, may be subject to pre-translational as well as translational and/or post-translational regulation.
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PMID:Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis. 774 59

Inter- and intraindividual variability in pharmacokinetics of most drugs is largely determined by variable liver function as described by parameters of hepatic blood flow and metabolic capacity. These parameters may be altered as a result of disease affecting the liver, genetic differences in metabolising enzymes, and various types of drug interactions, including enzyme induction, enzyme inhibition or down-regulation. With the now known large number of drug metabolising enzymes, their differential substrate specificity, and their differential induction or inhibition, each test substance of liver function should be used as a probe for its specific metabolising enzyme. Thus, the concept of model test-substances providing general information about liver function has severe limitations. To test the metabolic activity of several enzymes, either several test substances may be given (cocktail approach) or several metabolites of a single test substance may be analysed (metabolic fingerprint approach). The enzyme-specific analysis of liver function results in a preference for analysis of the metabolites rather than analysis of the clearance of the parent test substance. There are specific methods to quantify the activity of cytochrome P450 enzymes such as CYP1A2, CYP2C9, CYP2C19MEPH, CYP2D6, CYP2E1, and CYP3A, and phase II enzymes, such as glutathione S-transferases, glucuronyl-transferases or N-acetyltransferases, in vivo. Interactions based on competitive or noncompetitive inhibition should be analysed specifically for the cytochrome P450 enzyme involved. At least 5 different types of cytochrome P450 enzyme induction may result in major variability of hepatic function; this may be quantified by biochemical parameters, clearance methods, or highly enzyme-specific methods such as Western blot analysis or molecular biological techniques such as mRNA quantification in blood and tissues. Therapeutic drug monitoring is already implicitly used for quantification of the enzyme activities relevant for a specific drug. Selective impairment of hepatic enzymes due to gene mutations may have an effect on the pharmacokinetics of certain drugs similar to that caused by cirrhosis. Assessment of this heritable source of variability in liver function is possible by in vivo or ex vivo enzymological methods. For genetically polymorphic enzymes and carrier proteins involved in drug disposition, molecular genetic methods using a patient's blood sample may be used for classification of the individual into: (i) the impaired or poor metaboliser (homozygous deficient); (ii) the extensive (homozygous active) metaboliser group; and (iii) the moderately extensive metaboliser (heterozygous) group. For hepatic blood flow determinations, galactose or sorbitol given at relatively low doses may be much better indicators than the indocyanine green.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Assessment of liver metabolic function. Clinical implications. 798 3

Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models. Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites. The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood. CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite. Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues. The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance. Age and gender do not appear to affect the disposition of fluvastatin. CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors. Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively. The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance. In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo. In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac. The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin. These alterations have not been shown to be clinically significant. There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents. Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.
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PMID:Clinical pharmacokinetics of fluvastatin. 1136 92

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.
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PMID:Clinical significance of the cytochrome P450 2C19 genetic polymorphism. 1222 94

We have measured cytochrome P450 (CYP) activity in nearly 150 samples of human liver microsomes and 64 samples of cryopreserved human hepatocytes, and we have performed induction studies in over 90 preparations of cultured human hepatocytes. We have analyzed these data to examine whether the expression of CYP enzyme activity in liver microsomes and isolated hepatocytes or the inducibility of CYP enzymes in cultured hepatocytes is influenced by the gender, age, or ethnicity of the donor (the latter being limited to Caucasians, African Americans, and Hispanics due to a paucity of livers from Asian donors). In human liver microsomes, there were no statistically significant differences (P > 0.05) in CYP activity as a function of age, gender, or ethnicity with one exception. 7-Ethoxyresorufin O-dealkylase (CYP1A2) activity was greater in males than females, which is consistent with clinical observation. Liver microsomal testosterone 6beta-hydroxylase (CYP3A4) activity was slightly greater in females than males, but the difference was not significant. However, in cryopreserved human hepatocytes, the gender difference in CYP3A4 activity (females = twice males) did reach statistical significance, which supports the clinical observation that females metabolize certain CYP3A4 substrates faster than do males. Compared with those from Caucasians and African Americans, liver microsomes from Hispanics had about twice the average activity of CYP2A6, CYP2B6, and CYP2C8 and half the activity of CYP1A2, although this apparent ethnic difference may be a consequence of the relatively low number of Hispanic donors. Primary cultures of hepatocytes were treated with beta-naphthoflavone, an inducer of CYP1A2, phenobarbital or rifampin, both of which induce CYP2B6, CYP2C9, CYP2C19, and CYP3A4, albeit it to different extents. Induction of these CYP enzymes in freshly cultured hepatocytes did not appear to be influenced by the gender or age of the donor. Furthermore, CYP3A4 induction in hepatocytes isolated from cirrhotic liver was comparable to that in normal hepatocytes, which supports the "healthy hepatocyte, sick environment" hypothesis of liver cirrhosis. This review summarizes these findings and discusses their implications for the use of human liver microsomes and hepatocytes for in vitro studies of drug metabolism and enzyme induction, which play a key role in drug development.
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PMID:The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. 1536 37

Many drugs, including most antiarrhythmics (some of which are now of limited clinical use) are eliminated by the hepatic route. If liver function is impaired, it can be anticipated that hepatic clearance will be delayed, which can lead to more pronounced drug accumulation with multiple dosing. Consequently, the potential risks of adverse events could be increased, especially as antiarrhythmics have a narrow therapeutic index. The present review summarises the available pharmacokinetic data on the most popular antiarrhythmic drugs to identify the enzymes involved in the metabolism of the various agents and confirm whether liver disease affects their elimination. Despite long usage of some of these drugs (e.g. amiodarone, diltiazem, disopyramide, procainamide and quinidine), surprisingly few data are available in patients with liver disease, making it difficult to give recommendations for dosage adjustment. In contrast, for carvedilol, lidocaine (lignocaine), propafenone and verapamil, sufficient clinical studies have been performed. For these drugs, a marked decrease in systemic and/or oral clearance and significant prolongation of the elimination half-life have been documented, which should be counteracted by a 2- to 3-fold reduction of the dosage in patients with moderate to severe liver cirrhosis. For sotalol, disopyramide and procainamide, renal clearance contributes considerably to overall elimination, suggesting that dosage reductions are probably unnecessary in patients with liver disease as long as renal function is normal. The hepatically eliminated antiarrhythmics are metabolised mainly by different cytochrome P450 (CYP) isoenzymes (e.g. CYP3A4, CYP1A2, CYP2C9, CYP2D6) and partly also by conjugations. As the extent of impairment in clearance is in the same range for all of these agents, it could be assumed that they have a common vulnerability and that, consequently, hepatic dysfunction will affect CYP-mediated phase I pathways in a similar fashion. The severity of liver disease has been estimated clinically by the validated Pugh score, and functionally by calculation of the clearance of probe drugs (e.g. antipyrine). Both approaches can be helpful in estimating/predicting impairments in drug metabolism, including antiarrhythmics. In conclusion, hepatic impairment decreases the elimination of many antiarrhythmics to such an extent that dosage reductions are highly recommended in such populations, especially in patients with cirrhosis.
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PMID:Antiarrhythmics: elimination and dosage considerations in hepatic impairment. 1802 86

HMG-CoA reductase inhibitors (statins) are widely used to treat hypercholesterolemia. Among the adverse effects associated with these drugs are statin-associated myopathies, ranging from asymptomatic elevation of serum creatine kinase to fatal rhabdomyolysis. Fluvastatin-induced fatal rhabdomyolysis has not been previously reported. We describe here a patient with liver cirrhosis who experienced fluvastatin-induced fatal rhabdomyolysis. This patient had been treated with simvastatin (20 mg/day) for coronary artery disease and was switched to fluvastatin (20 mg/day) 10 days before admission. He was also taking aspirin, betaxolol, candesartan, lactulose, and entecavir. Rhabdomyolysis was complicated and continued to progress. He was treated with massive hydration, urine alkalization, intravenous furosemide, and continuous renal replacement therapy for acute renal failure, but eventually died due to rhabdomyolysis complicated by hepatic failure. In conclusion, fluvastatin should be used with caution in patients with liver cirrhosis, especially with other medications metabolized with CYP2C9.
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PMID:Fatal rhabdomyolysis in a patient with liver cirrhosis after switching from simvastatin to fluvastatin. 2214 3

There is increasing evidence that tyrosine kinase inhibitors (TKIs) have significant blood glucose lowering effects. A 70-year old Caucasian male with liver cirrhosis Child-Pugh A, advanced hepatocellular carcinoma and diabetes had a stable glycemic control being treated with glibenclamide (3.5 mg twice daily). After the first daily dose of the TKI sorafenib (800 mg) the patient experienced acute nocturnal disorientation and somnolence with a corresponding blood glucose of 37 mg/dl. After administration of glucose intravenously the neurological disturbances were completely reversible. As there was no intercurrent deterioration neither of hepatic nor of renal function, the severe hypoglycemia can likely be attributed to a drug-drug interaction of sorafenib with the sulfonylurea. The complete inhibition of the CYP2C9 and CYP3A4 mediated metabolic pathway of glibenclamide through sorafenib might have resulted in a rapid accumulation of glibenclamide. Profound blood glucose lowering effects of sorafenib might have additionally contributed to the hypoglycemic episode.
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PMID:Severe hypoglycemia due to possible interaction between glibenclamide and sorafenib in a patient with hepatocellular carcinoma. 2384 93

The aim of this study was to elucidate the effects of zedoary turmeric oil (ZTO) on P450 activities (CYP1A2, CYP2C9, CYP2C19, CYP2B6, CYP2D6 and CYP3A4) in rats with liver cirrhosis induced by thioacetamide (TAA). For the induction of liver cirrhosis, rats were given TAA in their drinking water at a concentration of 0.03% for consecutive 5 weeks and then 0.04% for the next consecutive 5 weeks throughout the establishment of cirrhosis. Then the cirrhotic rats were ip given saline, ZTO 100, 200 and 400 mg/kg, respectively, once daily for 2 weeks. When cirrhosis model was established at week 10, all rats of five groups were administered intragastrically with 15 mg/kg phenacetin, 0.6 mg/kg tolbutamide, 15 mg/kg omeprazole, 15 mg/kg bupropion, 15 mg/kg metoprolol, and 10 mg/kg midazolam. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The degree of liver cirrhosis was assessed by HE staining. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from the model group increased by approximately 4-fold, and a decreased level of albumin (Alb) was also observed, as compared to the control group (P < 0.05). However, ZTO was found to reverse those changes of serum levels observed in the model group, and the 200 mg/kg ZTO treatment group showed the most obvious reverse tendency with significantly decreased ALT, AST and increased Alb levels (P < 0.05). The results indicated that ZTO with the dose of 100 mg/kg could inhibit the activities of CYP450 isoforms CYP2C9 and CYP2D6 in vivo in cirrhotic rats induced by TAA, while ZTO with the dose of 400 mg/kg could induce the activity of CYP2C19 in vivo in cirrhotic rats induced by TAA. However, ZTO showed no influence on cirrhotic rat hepatic CYP1A2, CYP2B6 and CYP3A4 activity in vivo. This has certain guiding significance to clinical treatment.
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PMID:Effects of zedoary turmeric oil on P450 activities in rats with liver cirrhosis induced by thioacetamide. 2555 Aug 25

Hepatocellular carcinoma (HCC) accompanied by severe liver dysfunction is a serious disease, which results in altered hepatic clearance. Generally, maintenance doses depend upon drug clearance, so individual dosage regimens should be customized for HCC patients based on the condition of patients. Based on clearance of CYP isoform-specific substrates at the microsomal level (CLM), microsomal protein per gram of liver (MPPGL), liver weight, hepatic blood flow, hepatic clearance values (CLH) for 10 CYPs in HCC patients (n=102) were extrapolated using a predictive bottom-up pharmacokinetic model. Compared with controls, the CLM values for CYP2C9, 2D6, 2E1 were significantly increased in HCC patients. Additionally, CYP1A2, 2C8, 2C19 CLM values decreased while the values for CYP2A6, 2B6, 3A4/5 were unchanged. The MPPGL values in HCC tissues were significantly reduced. CLH values of HCC patients for CYP1A2, 2A6, 2B6, 2C8, 2C19, and 3A4/5 were significantly reduced, while this for CYP2E1 were markedly increased and those for CYP2C9 and 2D6 did not change. Moreover, disease (fibrosis and cirrhosis) and polymorphisms of the CYP genes have influenced the CLH for some CYPs. Prediction of the effects of HCC on drug clearance may be helpful for the design of clinical studies and the clinical management of drugs in HCC patients.
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PMID:Changes in cytochrome P450s-mediated drug clearance in patients with hepatocellular carcinoma in vitro and in vivo: a bottom-up approach. 2708 20


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