Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; OPC-13013) is a 2-oxo-quinoline derivative with antithrombotic, vasodilator, antimitogenic and cardiotonic properties. The compound is a potent inhibitor of phosphodiesterase (PDE) 3A, the isoform of PDE 3 in the cardiovascular system (IC50: 0.2 microM). In addition, there is inhibition of adenosine uptake, eventually resulting in changes in cAMP levels, dependent on the type of adenosine receptors (A1 or A2). Cilostazol inhibits platelet aggregation and has considerable antithrombotic effects in vivo. The compound relaxes vascular smooth muscle and inhibits mitogenesis and migration of vascular smooth muscle cells. In the heart, cilostazol causes positive inotropic and chronotropic effects. Most, if not all, of these actions are cAMP-mediated, including the modification of cAMP-controlled gene expression. Cilostazol decreases levels of serum triglycerides and causes some increase in HDL-cholesterol levels. The compound has a number of additional effects which might contribute to its overall clinical efficacy. Cilostazol undergoes intensive and finally complete hepatic metabolism via the cytochrome P450 systems. This might result in some drug interaction, i.e. with erythromycin and omeprazole. The half-life is approximately 10 h, resulting in about 2-fold accumulation of the drug during repeated administration.
Diabetes Obes Metab 2002 Mar
PMID:The pharmacology of cilostazol. 1218 Mar 53

Troglitazone (TRO) was developed for the treatment of type II diabetes. It was withdrawn from use due to idiosyncratic liver damage and failure. The mechanism of toxicity is still not determined, moreover, it is still not clear whether toxicity is due to the parent compound or its metabolite(s). The cytotoxicity of TRO was evaluated in human hepatocytes using previously cryopreserved hepatocyte suspensions from 27 human donors. Cellular adenosine triphosphate content was used as a viability endpoint. To investigate the role of xenobiotic metabolism in TRO toxicity, the correlation between the drug metabolism activities of the hepatocytes from each donor to EC(50) values TRO cytotoxicity. The activities examined were cytochrome P450 (CYP) isoform activities (CYP2A6, CYP2D6, CYP2C19, CYP1A2, CYP2E1, CYP3A4 and CYP2C9) and phase 2 conjugation enzyme activities (phenol sulfotransferase (PST) and glucuronyl transferase (UGT)). Taken individually, none of the phase 1 or 2 enzyme activities correlated to the EC(50). However, when three enzyme activities ((CYP3A4 x UGT)/PST) were taken into account, a correlation was made (r(2)=0.53). Based on the correlation, we hypothesize that TRO and TRO sulfate are direct acting toxicants, whereas CYP3A4 oxidation and glucuronidation are detoxification pathways.
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PMID:Correlation between troglitazone cytotoxicity and drug metabolic enzyme activities in cryopreserved human hepatocytes. 1239 56

Troglitazone (TGZ) is an orally active antihyperglycemic agent used in the treatment of noninsulin-dependent diabetes mellitus. Several cases of liver failure following TGZ administration led to its withdrawal from the market. The mechanism of toxicity is still not understood. The formation of toxic metabolites is believed to play an important role. Herein, we report the biotransformation of TGZ in human hepatocytes. TGZ at 50 microM concentration was incubated with cryopreserved human hepatocytes. Four metabolites were found-glucuronide, sulfate, and two glutathione (GSH) conjugates of TGZ. The two GSH metabolites could be conjugation at the 6-hydroxychromane nucleus and the thiazolidinedione ring. Alternatively, the conjugation could be one of the two rings, with the two GSH metabolites are diastereomers. The sulfate conjugate was the major metabolite found. The cytochrome P450 (CYP) inhibitors furafylline (CYP1A1/2), omeprazole (CYP2C19), ketoconazole (CYP3A4), and sulfaphenazole (CYP2C9) had no inhibitory effect on the TGZ metabolism suggesting that several P450s may play a role in the TGZ metabolic pathway. Previous studies in our laboratory have shown a large interindividual variation between different donors in cytotoxicity after dosing with TGZ. Based on EC(50) values, donors were classified as sensitive or resistant. The sensitive human donors were found to form significantly less troglitazone GSH conjugates and glucuronides than the resistant donors.
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PMID:Identification of glutathione conjugates of troglitazone in human hepatocytes. 1239 57

Treatment of HIV infection with potent combination antiretroviral therapy has resulted in major improvement in overall survival, immune function and the incidence of opportunistic infections. However, HIV infection and treatment has been associated with the development of metabolic complications, including hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia. Safe pharmacological treatment of these complications requires an understanding of the drug-drug interactions between antiretroviral drugs and the drugs used in the treatment of metabolic complications. Since formal studies of most of these interactions have not been performed, predictions must be based on our understanding of the metabolism of these agents. All HIV protease inhibitors are metabolised by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir is the most potent inhibitor of CYP3A4. Ritonavir and nelfinavir also induce a host of CYP isoforms as well as some conjugating enzymes. The non-nucleoside reverse transcriptase inhibitor delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4. Drug interaction studies have been performed with HIV protease inhibitors and HMG-CoA reductase inhibitors. Coadministration of ritonavir plus saquinavir to HIV-seronegative volunteers resulted in increased exposure to simvastatin acid by 3059%. Atorvastatin exposure increased by 347%, but exposure to active atorvastatin increased by only 79%. Conversely, pravastatin exposure decreased by 50%. Similar results have been obtained with combinations of simvastatin and atorvastatin with other HIV protease inhibitors. Thus, the lactone prodrugs simvastatin and lovastatin should not be used with HIV protease inhibitors. Atorvastatin may be used with caution. Although there are no formal studies available, calcium channel antagonists and repaglinide may have significant interactions and toxicity when used with HIV protease inhibitors because of their metabolism by CYP3A4. Sulfonylurea drugs utilise mainly CYP2C9 for metabolism, and this isoenzyme may be induced by ritonavir and nelfinavir with a resulting decrease in efficacy of the sulfonylurea. Losartan may have increased effect when coadministered with ritonavir and nelfinavir because of the induction of CYP2C9 and the expected increase in formation of the active metabolite, E-3174. Overall, well-designed drug-drug interaction studies at steady state are needed to determine whether antiretroviral drugs may be safely coadministered with many of the drugs used in the treatment of the metabolic complications of HIV infection.
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PMID:Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. 1240 66

Successful combination therapy with atypical antipsychotics and selective serotonin reuptake inhibitors has been reported for several psychiatric conditions. However, great attention should be paid to the possible adverse effects. In this retrospective chart review, we focused on the drug-drug interaction of paroxetine and risperidone. Retrospectively, we identified two patients treated with a combination of risperidone and paroxetine therapy, and analyzed their medical records. During a 3-month period of monotherapy with risperidone, the changes in body weight were +/- 0.0 kg in Patient 1 and -2.0 kg in Patient 2. In contrast, during combination therapy with paroxetine and risperidone, the body-weight changes were +14.0 kg in Patient 1 (after 4 months) and +13.5 kg in Patient 2 (after 5 months). In addition, diabetes mellitus was observed in Patient 2. Regarding the mechanism of severe weight gain in these two patients, we speculate a drug-drug interaction involving inhibition of the cytochrome P450 enzyme 2D6 (CYP4502D6) by paroxetine.
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PMID:Severe weight gain induced by combination treatment with risperidone and paroxetine. 1241 60

Genetic variations are playing an increasing role in drug discovery, particularly in disease-specific drug target identification and in drug candidate profiling to predict drug response in genetically heterogeneous patient populations. Recently, genetic studies have successfully contributed to the identification of new susceptibility genes, disease mechanisms and potentially novel disease-specific drug targets for common diseases such as Type II diabetes, Crohn's disease, asthma and osteoporosis. Numerous variants of cytochrome P450 enzymes and the pregnane X receptor, recently associated with protein expression and altered catalytic activities, may prove to be of use in the future in drug candidate profiling.
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PMID:The increasing importance of genetic variation in drug discovery and development. 1259 57

Rosiglitazone and pioglitazone are thiazolidinediones used for treatment of noninsulin-dependent diabetes mellitus. These compounds, along with troglitazone, were evaluated for the ability to induce cytochrome P450 enzymes (P450) in primary human hepatocyte cultures and to inhibit P450 in human microsomes. In induction studies, all three thiazolidinediones caused a dose-dependent increase in CYP3A4 activity and immunoreactive protein. While troglitazone was the most potent, rosiglitazone and pioglitazone generally exceeded troglitazone in absolute CYP3A4 activity achieved at concentrations > or =10 microM. A comparable concentration-dependent increase in CYP2B6 immunoreactive protein was observed with all three thiazolidinediones. Microarray analysis revealed rifampin > troglitazone > pioglitazone > rosiglitazone in terms of CYP3A4 mRNA induction potential with 10 microM compound. Inhibition studies conducted for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, and CYP2E1 showed troglitazone to be the most nonselective and potent inhibitor followed by rosiglitazone and pioglitazone. In vitro, the thiazolidinediones were strong inhibitors of CYP2C8, with K(i) values between 1.7 and 5.6 microM, and of CYP3A4, with K(i) values between 1.6 and 11.8 microM. Troglitazone, in addition, inhibited CYP2C9 (K(i) 0.6 microM). Although the inhibitory effects of the thiazolidinediones have not been demonstrated clinically, our results suggest there is potential for interactions with CYP2C8 substrates. This is the first report of in vitro induction of P450 enzymes by rosiglitazone and pioglitazone. While only the induction of CYP3A4 by troglitazone has been demonstrated in vivo, these results suggest that other thiazolidinediones may have the potential to cause clinically significant drug interactions at sufficiently high doses.
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PMID:Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. 1264 70

Renal vascular effects of cyclooxygenase and cytochrome P450 metabolites of arachidonic acid have been extensively studied, with major advances having been made. More recently, studies indicate that arachidonic acid metabolites of the lipoxygenase and cytochrome P450 pathway, such as hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids, play novel roles in glomerular mesangial and epithelial cells that are relevant to the pathogenesis of kidney disease associated with diabetes and hypertension. These studies demonstrate that eicosanoids generated during the actions of growth factors and vasoconstrictors can modulate disease processes by affecting vascular homeostasis, inflammation, cellular growth, apoptosis and oxidant stress. In addition, they highlight the important roles played by these oxidized lipids in mediating multiple physiological and pathological functions in the kidney through activation of key signal transduction pathways and genes.
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PMID:HETEs/EETs in renal glomerular and epithelial cell functions. 1268 Dec 44

The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to reduce major cardiovascular events in both primary and secondary prevention, and statins became one of the most widely prescribed classes of drugs throughout the world. Previously, statins have been well tolerated and have shown favorable safety profiles. However, the voluntary withdrawal of cerivastatin from the market because of a disproportionate number of reports of rhabdomyolysis-associated deaths drew attention to the pharmacokinetic profile of statins, which may possibly have been related to serious drug-drug interactions. Pitavastatin (NK-104, previously called itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) is a novel, fully synthetic statin, which has a potent cholesterol-lowering action. The short-term and long-term lipid-modifying effects of pitavastatin have already been investigated in subjects with primary hypercholesterolemia, heterozygous familial hypercholesterolemia, hypertriglyceridemia, and type-2 diabetes mellitus accompanied by hyperlipidemia. Within the range of daily doses from 1 to 4 mg, the efficacy of pitavastatin as a lipid-lowering drug seems to be similar, or potentially superior, to that of atorvastatin. According to the results of pharmacokinetic studies, pitavastatin showed favorable and promising safety profile; it was only slightly metabolized by the cytochrome P450 (CYP) system, its lactone form had no inhibitory effects on the CYP3A4-mediated metabolism of concomitantly administered drugs; P-glycoprotein-mediated transport did not play a major role in its disposition, and pitavastatin did not inhibit P-glycoprotein activity. It could be concluded that pitavastatin could provide a new and potentially better therapeutic choice for lipid-modifying therapy than do the currently available statins. The efficacy and safety of higher dose treatment, as well as its long-term effects in the prevention of coronary artery disease, should be further investigated.
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PMID:Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. 1293 Dec 54

Transplantation has transformed the treatment of patients with organ failure in a number of clinical settings, and immunosuppressive drug therapy is fundamental to its success. However, all the drugs in current use have a narrow therapeutic index. Under-dosing can lead to rejection, while over-dosing increases the risks of infection, malignant disease, and serious drug-specific adverse effects, including diabetes mellitus, nephrotoxicity, hypertension, and hyperlipidemia. Heterogeneity in the pharmacokinetics of these drugs makes initial dose determination difficult, as there is a poor correlation between dose and blood concentration. This results in difficulties in achieving target blood concentrations early after transplantation, which are important for reducing the rate of immunological rejection. This problem is compounded by the observation that neither drug dose nor drug blood concentration accurately predict clinical efficacy or toxicity. The main determinant of heterogeneity in dose requirements is intestinal absorption of the active drug. The oxidative enzymes, cytochrome P450 (CYP) 3A4 and CYP3A5, and the drug efflux pump P-glycoprotein (P-gp) in enterocytes regulate this process. Most substrates for the P-gp pump are also substrates for the CYP3A enzymes. An efficient barrier to xenobiotic absorption is formed by the CYP enzymes and P-gp, and by the two systems working synergistically. Genetic polymorphisms have been reported for the genes associated with the expression of the CYP3A enzymes and P-gp. Genotyping patients for CYP3A genes has the potential to aid the establishment of optimal dosage regimens for transplant patients. Genetic polymorphism of the multiple drug resistance gene-1 (MDR1, also known as ABCB1) [3435C/T] and the CYP3A5 genes (CYP3A5*1, CYP3AP1*1) have the greatest potential to influence the pharmacokinetics of immunosuppressants. Homozygosity of the T allele of the MDR1 3435C/T polymorphism has been associated with reduced enterocyte expression of P-gp resulting in increased drug absorption. The presence of the CYP3A5*1 allele is necessary for the production of a fully catalytic CYP3A5 protein, and also influences the ratio of CYP3A4 : CYP3A5 as well as the overall CYP3A catalytic activity. The CYP3A4 : CYP3A5 ratio may, in turn, influence the pattern of drug metabolites formed. Heterogeneity in the production of active and inactive metabolites has implications for both the pharmacokinetics and pharmacodynamics of these drugs.Gene frequencies and drug dose requirements differ between ethnic groups. Ethnic differences in dose requirements for immunosuppressants have been discussed widely. However, ethnicity is a rather crude marker for genotype. Pharmacogenetic typing offers the possibility of significant improvement in the individualization of immunosuppressive drug prescribing with reduced rates of rejection and toxicity.
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PMID:The pharmacogenetics of immunosuppression for organ transplantation: a route to individualization of drug administration. 1457 18


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