Current Drug Metabolism - Volume 10, Issue 2, 2009

Levosimendan, a Ca2+ sensitizer, has emerged as an alternative option of pharmacologic inotropic support in patients with decompensated heart failure. In contrast to classic inotropes, rather than interfering with intracellular Ca2+ levels in myocytes, levosimendan improves cardiac performance via Ca2+ sensitization and K+ channel-mediated peripheral vasodilatation. A two compartment pharmacokinetic model with zero-order input and first-order elimination has been found to describe best the pharmacokinetics of levosimendan. Although oral levosimendan has high bioavailability (≈85%), in clinical practice it has been hitherto administered intravenously. Levosimendan has total clearance 175-250 mL/h/kg and most importantly a short half-life (about 1.5 hours). Therefore, this drug has a special pharmacokinetic interest: It is one of the few drugs used in cardiovascular medicine, whose prolonged action is not due to the drug itself but it is mainly due to its active metabolite OR-1896 (∼80 hours half life). Other metabolites with possible pharmacologic effect are N-conjugated OR-1855 (M7), N-hydroxylated OR-1855 (M8), N-hydroxylated OR-1896 (M10), O-glucuronide OR-1896 (M9) and O-sulfate (M11) of N-hydroxylated OR-1896. Initial reports on levosimendan's use in severe heart failure were positive and levosimendan has already been routinely used for the treatment of patients with decompensated heart failure, while it has been included to the European Society of Cardiology guidelines for the treatment of acute heart failure (class of recommendation IIb, level of evidence B). However, recent clinical trials have failed to demonstrate a clear benefit of levosimendan on survival, compared to other classic inotropic agents in patients requiring inotropic support. In this review article we provide a pharmacokinetic approach for the use of levosimendan in cardiovascular system by discussing its metabolism and mainly the pharmacology of its active metabolites in humans.

Cytochrome P450 (CYP) is a diverse superfamily of hemoproteins found in a large number of organisms. Most cytochrome P450 enzymes have monooxygenase activity and are involved in detoxification and hormone and lipid metabolism. In drug metabolism, the chemical modification or degradation of chemicals including exogenous and endogenous compounds, cytochrome P450 is probably the most important element of oxidative metabolism. The present understanding of the mechanisms of induction of cytochrome P450 enzymes and their regulation has made considerable progress during the last few years. However, it remains the subject of intense scientific research to better understand how the expression of cytochrome P450 enzymes is regulated at the molecular level. It has been known for three decades that the expression of cytochrome P450 gene family members is regulated by the biological clock. In addition, hepatic P450 monooxygenases metabolize melatonin, the pineal hormone whose expression is controlled by the biological clock and, in turn, resets the biological clock. This review will summarize our present understanding on how the biological clock regulates the expression and activity of cytochrome P450 enzymes to affect pharmacokinetics and detoxification and hormone and lipid metabolism and how melatonin metabolism and cytochrome P450 enzyme activity can affect circadian rhythms in mammals.

In last few years, the use of zebrafish (Danio rerio) in scientific research is growing very rapidly. Initially, it was a popular as a model of vertebrate development because zebrafish embryos are transparent and also develop rapidly. Presently, the research using zebrafish is expanding into other areas such as pharmacology, clinical research as a diseases model and interestingly in drug discovery. The use of zebrafish in pharmaceutical research and discovery and drug development is mainly screening of lead compounds, target identification, target validation, morpholino oligonucleotide screens, assay development for drug discovery, physiology based drug discovery, quantitative structure-activity relationship (QSAR) and structure -activity relationships (SAR) study and drug toxicity study. In this paper, we have described properly all the areas of dug discovery where zebrafish is used as a tool. We are hopeful that the use of these techniques or methods will make the zebrafish a prominent model in drug discovery and development research in the forthcoming years.

The enteroinsular axis (EIA) constitutes a physiological signalling system whereby intestinal endocrine cells secrete incretin hormones following feeding that potentiate insulin secretion and contribute to the regulation of blood glucose homeostasis. The two key hormones responsible are named glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Recent years have witnessed sustained development of antidiabetic therapies that exploit the EIA. Current clinical compounds divide neatly into two classes. One concerns analogues or mimetics of GLP-1, such as exenatide (Byetta) or liraglutide (NN2211). The other group comprises the gliptins (e.g. sitagliptin and vildagliptin) which boost endogenous incretin activity by inhibiting the enzyme dipeptidyl peptidase 4 (DPP 4) that degrades both GLP-1 and GIP. Ongoing research indicates that further incretin and gliptin compounds will become available for clinical use in the near future, offering comparable or improved efficacy. For incretin analogues there is the prospect of prolonged duration of action and alternative routes of administration. This review focuses on recent advances in pre-clinical research and their translation into clinical studies to provide future therapies for type 2 diabetes targeting the EIA.

Signaling through the Ha-Ras/ mitogen-activated protein kinase cascade and through the Wnt/ β-catenin signaling pathway has been implicated in various developmental processes as well as in carcinogenesis of different organs by regulating cell growth and differentiation. In particular, both pathways have been reported to play an important role in embryonic liver development as well as in liver regeneration after partial hepatectomy. More recently, there is accumulating evidence for a role of Ras- and β-catenin-dependent signal transduction in the regulation of zone-specific gene expression in healthy adult liver. An antagonistic interplay of both pathways was proposed: β-catenin was established to function as a decisive regulator of ‘perivenous’ gene expression in hepatocytes neighboring branches of the central vein, whereas the Ras pathway was linked to transcription of ‘periportal’ genes. Xenobiotic-metabolizing enzymes constitute one of the largest functionally related groups of zonated genes with predominantly perivenous expression of the most abundant enzymes of xenobiotic metabolism. In this review, the current knowledge regarding the role of Ras and β-catenin signaling in the regulation of expression of xenobiotic-metabolizing enzymes from the cytochrome P450 superfamily will be summarized including both in vitro and in vivo observations.

Diabetes is associated with an increase risk for cardiovascular disease (CVD). Recently, macrovascular complications of diabetes have been shown to start before the development of diabetes. Indeed, several clinical studies have confirmed the increased risk of CVD in patients with impaired glucose tolerance (IGT). Since postprandial hyperglycemia and insulin resistance are thought to play a central role in the development and progression of CVD in patients with IGT, amelioration of postprandial hyperglycemia as well as insulin resistance is a therapeutic target for the prevention of CVD in these high-risk patients. Acarbose, an α-glucosidase inhibitor, delays the absorption of carbohydrate from the small intestine, thereby reducing postprandial hyperglycemia. Further, recently, acarbose has been shown to improve insulin resistance in vivo. These findings suggest that acarbose is a promising metabolic modifier that could reduce the risk of CVD in patients with the metabolic syndrome. In this paper, we review the clinical utility of acarbose in various cardiometabolic disorders.

Nuclear factor kappa B (NF-κB) is an important transcription factor that regulates a wide spectrum of genes including cytochrome P450 (CYP), the most important family of drug metabolizing enzymes. Therefore, in this review, we addressed the potential role of NF-κB in CYP regulation. We proposed three mechanisms by which NF-κB can regulate CYP expression and activity. First, NF-κB can directly regulate the expression of CYP1A1, CYP2B1/2, CYP2C11, CYP2D5, CYP2E1, CYP3A7, and CYP27B1 through binding to the promoter region of these genes. Second, NF-κB indirectly regulates the transcription of CYP genes through mutual repression with some nuclear receptors that are involved in CYP regulation such as AhR, CAR, GR, PXR, RXR, PPAR, FXR, and LXR. Finally, NF-κB can regulate CYP activity at post-transcriptional level by inducing heme oxygenase or by affecting the CYP protein stability. In addition, increased inflammatory mediators, oxidative stress, and subsequent NF-κB activation have been demonstrated in many conditions such as inflammatory bowel diseases, rheumatoid arthritis, psychological stress, diabetes, aging, cancer, renal diseases, and congestive heart failure. Meanwhile, there is a significant alteration of CYP expression and activity in these diseases. Therefore, we propose that NF-κB could be one of the links between inflammation, oxidative stress, and CYP regulation in these diseases. In conclusion, NF-κB plays a crucial role in the regulation of CYP through several mechanisms and this role can explain the altered CYP regulation in many conditions.

Mycophenolate mofetil (MMF) is the preferred antimetabolite in solid organ transplantation. It is a prodrug that undergoes pre-systemic metabolism to mycophenolic acid (MPA), the active drug moiety. MMF is typically administered as a fixed dose without routine monitoring of MPA concentrations. However, a role for therapeutic drug monitoring (TDM) of MPA has been suggested based on the drug's narrow therapeutic window and considerable between-subject variability. Dose-normalized MPA area under the concentration- time curve (AUC) has been observed to vary ≥10-fold. Some of this variability may be accounted for by patient variability in renal and liver function, serum albumin and haemoglobin levels, body mass, concomitant medication exposure and genetic polymorphisms in enzymes responsible for drug metabolism and transport, but much is unexplained. Widespread adoption of MPA TDM has been limited by the impracticality of full 0 to 12 hour AUC measurement (AUC0-12), poor correlation between pre-dose MPA concentration and AUC0- 12, ongoing questions regarding the utility of free versus total MPA measurements and lack of evidence correlating MPA exposure with clinical outcomes. Two recent randomized studies evaluating the role of MPA TDM in renal transplant recipients have reported conflicting results. Promising areas of ongoing study include use of Bayesian forecasting to predict MPA dosage and measurement of inosine monophosphate dehydrogenase activity. This review provides an overview of the pharmacokinetics of MMF in solid organ transplantation, and discusses the benefits and limitations of MPA monitoring. Areas that require additional research are identified.

About 50% of therapeutic drugs are currently administered as a racemate, a mixture of equal proportions of two enantiomers. In an achiral environment, the enantiomers of a chiral drug show identical chemical and physical properties. However, they can present different chemical and pharmacological behavior in a chiral environment such as in the body. The interaction of two enantiomers with a chiral macromolecule, such as an enzyme or receptor, is three dimensional in nature, forming diastereomeric complexes resulting in a chiral recognition process. Moreover, when administered as a racemate, two enantiomers can display the pharmacokinetic processes (absorption, distribution, metabolism and excretion) in a stereoselective manner. Among these processes, stereoselectivity plays a central role in the metabolism due to the involvement of the enzymatic system. Thus, the purpose of the current review is to present important aspects related to stereochemistry of drug metabolism, with emphasis on molecular mechanisms involved in enzyme mediated reactions, such as those catalyzed by cytochrome P450, uridine 5'-diphospho (UDP)-glucuronosyltransferases and sulfotransferases. Additionally, recent advances regarding the analysis of chiral drugs and their metabolites employing different analytical techniques (high-performance liquid chromatography-HPLC and capillary electrophoresis-CE) will also be outlined.