Current Drug Metabolism (v.14, #10)

Biotransformation of Silybin and its Congeners by Vladimír Kren, Petr Marhol, Katerina Purchartová, Eva Gabrielová, Martin Modriansky (1009-1021).
Silybin and its congeners belong to a group of flavonolignans with strong biological activities. These compounds arepotentially applicable in human medicine, e. g. due to their cytoprotective activity. As a part of herbal preparations available on the openmarket, they face the risk of potential negative drug-drug interactions. This review aims to evaluate current knowledge on the metabolismof these compounds by biotransformation enzymes, interactions with other drugs, their pharmacokinetics, and bioavailability. Whilesilybin and its derivatives interact with cytochrome P450s, only metabolism of silybin by cytochrome P450 2C8 poses a risk of adverseeffects. The main biotransformation route of silybin and derivatives was identified as conjugation, which is stereospecific in case ofsilybin. Studies of the metabolism, pharmacokinetics, potentional drug - drug interactions and increasing bioavailability of these flavonolignansplay an important facet of possible therapeutical use of these compounds. The goal of our review is to aid future developments inthe area of silybin research.

The liver is a vital organ in vertebrates that can be subject to disease, among others due to exposure to toxic xenobioticcompounds. A group of transcription factors named ligand activated nuclear receptors (LANR) influence and regulate important liverfunctions, and can be activated by many xenobiotic compounds, which thereby can cause hepatotoxicity. Systematic analysis of the genepathways regulated by LANR using modern 'omics technologies is important for investigating modes-of-action of hepatotoxicants. Sofar, these pathways are not publicly available in a format that allows these studies.;We used PathVisio to build liver-specific LANR pathways, both for rats and humans. Since many LANR pathways are linked to eachother, we also merged them into a meta-pathway. The pathways are in a GPML-format that enables pathway statistics and visualisations,and will be made available to the public through WikiPathways. We demonstrate the performance of these novel pathways in evaluatingtranscriptomic studies from the Japanese toxicogenomics project database (Open TG-GATEs).;We show that the new pathways can be used to accurately analyse and visualize the effects of prototypical hepatotoxicants in importantliver processes, and thus to evaluate the possible mode-of-actions of hepatotoxic xenobiotic compounds by assessing which LANRs arepossible targets.

Although arsenic is known to cause cancers of lung, skin and kidney, arsenic trioxide (As2O3) has been recently recognized asone of the most effective novel anticancer agent for the treatment of acute promyelocytic leukemia (APL). These paradoxical effects ofarsenic may be dose-dependent, associated with its distinctive metabolism, or correlated with its direct or indirect effects on differentcellular pathways which may result in altered cellular functions. The basic mechanism through which As2O3 induces molecular remissionin APL patients include direct targeting of PML and retinoic acid receptor alpha fusion protein (PML-RARα) by arsenic resulting inoncoprotein degradation leading to partial differentiation. Many in vitro studies have also indicated that the anticancer properties ofAs2O3 against non-APL blood cancers predominantly occur through induction of apoptotic pathway. Especially, release of cytochrome cor activation of the caspase cascades and apoptosis-related proteins by arsenic is thought to occur by directly targeting mitochondria. Themechanisms and the selective target sites that have been usually associated with the cytotoxic effects of arsenicals are discussed here withreference to their contribution towards the anticancer properties of arsenic. In this review we have particularly explained the in vivoor in vitro arsenic toxicity based on arsenic metabolic pathway and its different metabolites. These multiple effects and different selectivetarget sites for arsenic and its metabolites emphasize the need for better understanding of paradoxical effects of arsenic which mayprovide the appropriate use of this agent in the treatment of various malignancies.

Enrofloxacin: Pharmacokinetics and Metabolism in Domestic Animal Species by Cristina López-Cadenas, Matilde Sierra-Vega, Juan J. García-Vieitez, M. José Diez-Liébana, Ana Sahagún-Prieto, Nélida Fernández- Martínez (1042-1058).
Enrofloxacin is a fluorquinolone exclusively developed for use in veterinary medicine (1980). The kinetics of enrofloxacin arecharacterized, in general terms, by high bioavailability in most species and rapid absorption after IM, SC or oral administration. However,several studies reported that enrofloxacin showed low bioavailability after oral administration in ruminants. This drug has a broaddistribution in the organism, excellent tissue penetration and long serum half-life. Also, enrofloxacin is characterized by a low host toxicity,a broad antibacterial spectrum and high bactericidal activity against major pathogenic bacteria (both Gram-positive and Gramnegative),and intracellular organisms found in diseased animals. The kinetics vary according to the route of administration, formulation,animal species, age, body condition, and physiological status, all of which contribute to differences in drug efficacy. The pharmacokineticproperties of drugs are closely related to their pharmacological efficiency, so it is important to know their behavior in each speciesthat is used. This article reviews the pharmacokinetics of enrofloxacin in several domestic animal species.

Pregnane X receptor (PXR) is a member of the nuclear receptor (NR) superfamily of ligand-activated transcription factors andis activated by a huge variety of endobiotics and xenobiotics, including many clinical drugs. PXR plays key roles not only as a xenosensor inthe regulation of both major phase I and II drug metabolism and transporters but also as a physiological sensor in the modulation of bileacid and cholesterol metabolism, glucose and lipid metabolism, and bone and endocrine homeostasis.;Post-translational modifications such as phosphorylation have been shown to modulate the activity of many NRs, including PXR, andconstitute an important mechanism for crosstalk between signaling pathways and regulation of genes involved in both xenobiotic andendobiotic metabolism. In addition, microRNAs have recently been shown to constitute another level of PXR activity regulation.;The objective of this review is to comprehensively summarize current understanding of post-transcriptional and post-translationalmodifications of PXR in regulation of xenobiotic-metabolizing cytochrome P450 (CYP) genes, mainly in hepatic tissue. We also discussthe importance of PXR in crosstalk with cell signaling pathways, which at the level of transcription modify expression of genes associatedwith some physiological and pathological stages in the organs. Finally, we indicate that these PXR modifications may have importantimpacts on CYP-mediated biotransformation of some clinically used drugs.

Pharmacogenetic Variation and Metformin Response by Suning Chen, Jie Zhou, Miaomiao Xi, Yanyan Jia, Yan Wong, Jinyi Zhao, Likun Ding, Jian Zhang, Aidong Wen (1070-1082).
Diabetes is a major health problem worldwide, and metformin, a traditional oral anti-hyperglycemic drug, is now believed tobe the most widely prescribed antidiabetic drug. Metformin acts primarily by inhibiting hepatic glucose production and improving insulinsensitivity. Metformin is absorbed predominately by the small intestine and excreted in an unaltered form in the urine. The pharmacokineticsof metformin is primarily determined by membrane transporters, including the plasma membrane monoamine transporter (PMAT),the organic cation transporters (OCTs), the multidrug and toxin extrusion (MATE) transporters, and the critical protein kinase AMPactivatedprotein kinase (AMPK). PMAT may play a role in the uptake of metformin from the gastrointestinal tract, while OCTs mediatethe intestinal absorption, hepatic uptake, and renal excretion of metformin. MATEs are believed to contribute to the hepatic and renal excretionof the drug. The pharmacologic effects of metformin are primarily exerted in the liver, at least partly via the activation of AMPKand the subsequent inhibition of gluconeogenesis. A considerable amount of pharmacogenetic research has demonstrated that geneticvariation is one of the major factors affecting metformin response. Moreover, it has become increasingly clear that membrane transportersare important determinants of the pharmacokinetics of metformin. In this review, we will discuss the genetic variants of major transportersthat purportedly determine the pharmacokinetics of metformin in terms of drug bioavailability, distribution, and excretion, such asPMAT, OCTs, and MATEs. Understanding how genetic variation affects metformin response will help promote more effective use of thedrug for the treatment of type 2 diabetes (T2D).

Biotransformations of Prenylated Hop Flavonoids for Drug Discovery and Production by Agnieszka Bartmanska, Tomasz Tronina, Jaroslaw Poplonski, Ewa Huszcza (1083-1097).
In this review we aim to present current knowledge on biotransformation of flavonoids from hop cones with respect to type ofproduct, catalyst and conversion. Subsequently, a comparative analysis of biological activity of prenylated hop flavonoids and theirbiotransformation products has been performed in order to indicate these research efforts that have good potential for application inpharmaceutical industry. There is increasing evidence that the products of biotransformation of hop prenylflavonoids, which have beenlittle studied until recently, can be used as drugs or drug ingredients and also as standards of human drug metabolites. They can also serveas an inspiration for the design and chemical synthesis of new derivatives with higher or different biological activity. Nevertheless, muchadditional work, among others on determining the mechanism of action in in vivo systems, is needed to open up the way to biomedicalapplication of these compounds.