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Chu, Xiaoyan; Bleasby, Kelly; Evers, Raymond
doi: 10.1517/17425255.2013.741589pmid: 23256482
Introduction: Drug transporters play an important role in the absorption, distribution, and excretion (ADE) of many drugs. In the last several years it has become increasingly clear that there are significant differences between rodents, dog, monkey, and human in the substrate specificity, tissue distribution, and relative abundance of transporters. These differences complicate cross-species extrapolations, which is important when attempting to predict human pharmacokinetics (PK) of drug candidates and assess risk for drug–drug interactions (DDIs). Areas covered: This article provides an overview of species differences for the major transporters involved in drug disposition. Specifically, the article looks at a number of efflux and uptake transporters including multidrug resistance protein MDR1 P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), multidrug resistance proteins (MRPs), members of the multidrug resistance and toxic extrusion protein (MATE) family, as well as members of organic anion transporting polypeptides (OATPs), organic anion transporters (OATs), and organic cation transporters (OCTs). Expert opinion: Quantitative knowledge of species differences of transporters, especially at the protein and functional level is still limited. The current challenge is to extrapolate and integrate data from both preclinical species and humans to quantitatively predict the impact of transporters on drug absorption, disposition, and drug–drug interactions. Increased understanding of species differences in transporter expression and functional activity is needed in order to translate findings from preclinical species to humans. Ultimately, high quality in vitro and in vivo data will aid in the establishment of physiologically based pharmacokinetic (PBPK) models, which will improve the capability to predict PK characteristics of drug candidates in humans.
Chai, Xiaojuan; Zeng, Su; Xie, Wen
doi: 10.1517/17425255.2013.754010pmid: 23327618
Introduction: ‘Orphan' nuclear receptors belong to the nuclear receptor (NR) superfamily of transcriptional factors. Binding of ligands to these receptors results in the recruitment of the co-activators, thereby regulating the expression of cognate target genes. Areas covered: This review discusses the transcriptional regulation of P450 genes by two major xenobiotic nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Additional PXR and CAR target genes include those encoded for UDP-glucuronosyltransferases, glutathione S-transferases, sulfotransferases and drug transporters. The authors discuss the involvement of PXR and CAR in endobiotic metabolism. They also review the polymorphisms of PXR and CAR. Expert opinion: PXR and CAR are both xenobiotic and endobiotic receptors. A remarkably diverse set of chemicals can activate PXR and CAR. There is significant cross-talk among xenobiotic receptors. Future studies are needed to focus on the polymorphisms of the nuclear receptors and the complex regulatory networks among nuclear receptors. Considerations should be given while designing PXR- or CAR-targeting pharmaceutics to avoid adverse drug effects. In the meantime, due to the diverse functions of PXR and CAR, agonists or antagonists for these receptors may have therapeutic potentials in managing certain diseases and enhancing therapeutic indexes.
doi: 10.1517/17425255.2013.749858pmid: 23289831
Introduction: The flavonoids are a large group of dietary plant compounds with suggested health benefits. There is accumulating evidence that many of these flavonoids can interact with the major drug transporters (and metabolizing enzymes) in the body, leading to alterations in the pharmacokinetics of substrate drugs, and thus their efficacy and toxicity. Areas covered: This review summarizes and updates the reported in vitro and in vivo interactions between common dietary flavonoids and the major drug-effluxing ABC transporters; these include P-glycoprotein, breast cancer resistance protein and multidrug resistance proteins 1 and 2. In contrast to previous reviews, the ADME of flavonoids are considered, along with their glycosides and Phase II conjugates. The authors also consider their possible interactions with the ABC transporters in the oral absorption, distribution into pharmacological sanctuaries and excretion of substrate drugs. Electronic databases, including PubMed, Scopus and Google Scholar were searched to identify appropriate in vitro and in vivo ABC transporter–flavonoid interactions, particularly within the last 10 years. Expert opinion: Caution is advised when taking flavonoid-containing supplements or herbal remedies concurrently with drugs. Further clinical studies are warranted to explore the impact of flavonoids and their metabolites on the pharmacokinetics, efficacy and toxicity of drugs.
Schnepf, Rebecca; Zolk, Oliver
doi: 10.1517/17425255.2013.742063pmid: 23289909
Introduction: The ATP-binding cassette transporter ABCG2 can actively extrude a broad range of endogenous and exogenous substrates across biological membranes. Thereby, ABCG2 limits oral drug bioavailability, mediates hepatobiliary and renal excretion and participates functionally in the blood-brain barrier. Areas covered: The paper provides a review of the clinical evidence of the role of ABCG2 in the bioavailability and brain disposition of drugs. It also sheds light on the value of experimental/preclinical data in predicting the role of ABCG2 in pharmacokinetics in humans. Expert opinion: Experimental studies indicate that ABCG2 may limit the oral bioavailability and brain penetration of many drugs. ABCG2 has also been recognized as an important determinant of the disposition of some drugs in humans. For example, loss-of-function variants of ABCG2 affect the pharmacokinetics and pharmacodynamics of rosuvastatin in a clinically significant manner. Moreover, clinically relevant pharmacokinetic drug–drug interactions have been attributed to ABCG2 inhibition. However, examples from human studies are still rare compared with the overwhelming evidence from experimental studies. The large degree of functional redundancy of ABCG2 with other transporters such as P-glycoprotein may explain the rare occurrence of ABCG2-dependent drug–drug interactions in humans. Providing clinicians with consolidated information on the clinically relevant interactions of drugs with ABCG2 remains a matter of future exploration.
Fareed, Jawed; Jeske, Walter; Thethi, Indermohan
doi: 10.1517/17425255.2013.749238pmid: 23289968
Introduction: Antithrombotics are one of the most commonly prescribed classes of medication around the world. The thienopyridines are an integral part of antithrombotic therapy and are prescribed for various indications including acute coronary syndrome, peripheral vascular disease and cerebrovascular disease. These drugs have distinct metabolic pathways, which lead to the formation of active metabolites that produce both observed clinical differences as well as pharmacokinetic and pharmacodynamic differences in response. Areas covered: The authors describe the pharmacokinetic and pharmacodynamic behavior of three of the currently available thienopyridines, namely ticlopidine, clopidogrel and prasugrel. The authors also describe and discuss the drug interaction and pharmacogenomic factors which may impact safety and drug efficacy. Expert opinion: P2Y12-ADP receptor antagonism has proven to be effective at preventing thrombosis. Differences in the activation of these drugs, cytochrome metabolism, concomitant drug use and pharmacogenomics have an impact on thienopyridine use. Clopidogrel remains the thienopyridine drug with the most approved indications for use. Prasugrel has proven to be efficacious but is associated with a higher bleeding risk in comparison to clopidogrel and therefore has to be used in appropriate clinical indications.
Kim, Young Mi; Park, Tae-Sik; Kim, Sang Geon
doi: 10.1517/17425255.2013.748749pmid: 23289866
Introduction: Sphingolipids represent a diverse class of lipid molecules. In addition to their function as membrane structural components, they serve as signaling molecules involved in various biological processes such as cell metabolism, growth, differentiation, stress and inflammatory responses and apoptosis. Sphingolipids may modulate the activity and/or expression of cytochrome P450s (CYPs) and transporters, which suggests that they may affect drug metabolism and excretion. Areas covered: In this review, the authors provide an overview of the properties of sphingolipid structures and metabolism. They also describe the effects of sphingolipids on the activity and expression of CYPs and transporters. In addition, the authors discuss the pathologic conditions where the sphingolipid metabolism is dysregulated particularly in association with inflammation and cancer. Expert opinion: Sphingolipidomic approaches have become accessible with the aid of advances in analytical technology. Sphingolipid profiles are modified by diseases, genetic disorders or certain drug treatment. The consequent changes in sphingolipid contents may alter the activities of detoxifying enzymes and those associated with cell viability. Since CYPs and transporters play roles in xenobiotics metabolism and excretion, sphingolipidomic information may be of use in understanding drug effect and toxicity.
doi: 10.1517/17425255.2013.737319pmid: 23157726
Introduction: Among the dimethanesulfonates, busulfan, in combination with other alkylating agents or nucleoside analogues, is the cornerstone of high-dose chemotherapy. It is used, and followed hematopoietic stem cell transplantation, for the treatment of various hematologic malignancies and immunodeficiencies. Treosulfan, which is a hydrophilic analogue of busulfan, was the first dimethanesufonate registered for the treatment of ovarian cancer. Recently, treosulfan has been investigated for the treatment of hematologic malignancies in combination with the same second agents before hematopoietic stem cell transplantation. Areas covered: This work reviews the pharmacological data of these two dimethanesulfonates alkylating agents. Specifically, the article looks at their chemistry, metabolism, anticancer activity, and their pharmacokinetics and pharmacodynamics. Expert opinion: Busulfan has been investigated widely for more than three decades leading to a large and precise handling of this agent with numerous studies on activity and pharmacokinetics and pharmacodynamics. In contrast, the behavior of treosulfan is still under investigation and not fully described. The complexity of treosulfan's metabolism and mechanism of action gives rise to the need of a deeper understanding of its pharmacological activity in a context of high-dose chemotherapy. Specifically, there is a great need to better understand its pharmacokinetics/pharmacodynamics relationship.
Kubiak, Xavier; Dairou, Julien; Dupret, Jean-Marie; Rodrigues-Lima, Fernando
doi: 10.1517/17425255.2013.742505pmid: 23289949
Introduction: Arylamine N-acetyltransferases (NATs) are polymorphic xenobiotic metabolizing enzymes catalyzing the acetylation of aromatic amine chemicals of pharmacological/toxicological relevance (drugs, carcinogens). NATs are primordial determinants of the detoxification and/or bioactivation of these compounds. These enzymes are found in prokaryotes and eukaryotes. Several NAT isoenzymes may be present in one organism, and their substrate specificity profile and pattern of tissue expression suggest distinct functional roles. Areas covered: Many advances in NAT mechanism, substrate specificity, and functional impact of polymorphism have come from crystallographic and NMR studies. To date, the crystal structures of 10 different NAT homologues have been solved, including two human isoforms and several bacterial NATs. The authors present the most recent snapshot in NAT structure differences and similarities. The authors also depict the structural bases of substrate/inhibitor recognition and specificity, cofactor binding, catalytic mechanism, genetic regulation (polymorphism), and enzyme inhibition. Expert opinion: The determination of other NATs structures will help to develop specific inhibitors of NAT enzymes with potential clinical relevance. In addition, it will contribute to the identification of endogenous substrates and novel functions associated to this family of enzymes.
doi: 10.1517/17425255.2013.767892pmid: 23373842
Introduction: The first-choice drug therapy in the management of type 2 diabetes is metformin. However, most patients require a combined therapy to reach and/or maintain targets of glucose control. Dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly referred to as gliptins, offer new options for combined therapy with metformin. Linagliptin is the most recently launched gliptin, with a unique pharmacokinetic (PK) profile characterized by negligible renal excretion and is now also available as a fixed-dose combination (FDC) with metformin. Areas covered: An extensive literature search was performed to analyze the potential PK and pharmacodynamic interactions between linagliptin and metformin. Linagliptin and metformin may be administered together, either separately or as FDC supported by bioequivalence studies. Linagliptin and metformin are not prone to PK drug–drug interactions. Their coadministration improves blood glucose control more potently than either compound separately, without hypoglycemia and without increasing metformin-related gastrointestinal side effects. Expert opinion: The combination linaglitpin plus metformin, if not contraindicated (renal failure), may be used as first-line or second-line therapy in the management of type 2 diabetes. That being said, the durability of the glucose-lowering effect of this combination needs to be further explored in long-term controlled trials.
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