Drug Delivery System Vol. 29(2014) No. 5
Promotion of Innovative Medicinal and Medical Sciences

Systems biology is an inter-disciplinary research field trying to understand biological complexity as systems. Cooperation between dry research and wet research is necessary to promote systems biology, i.e. technologies of computational science, such as development of detailed models, complicated simulations, and sophisticated data analyses, are playing important roles. Supports from consolidated software platform is essential. In this article we will introduce several software which can be helpful for promoting systems biology, including software that we have been developing.

Systems pharmacology brings the approaches of systems biology to the field of pharmacology. It seeks to understand drug actions and side effects in the context of the biological complex systems. Simulation studies in systems pharmacology are becoming an increasingly essential tool for proper in vitro-in vivo extrapolation so that we can understand in vivo consequences upon administration of drugs to humans. In addition, it may make a suggestion about new targets and strategies for therapeutics of complex diseases. Principle of systems pharmacology therefore seems to make major contributions to drug discovery and development. During recent years, there have been attempts to formulate the effects of drug on ion channels and to understand the actions and side effects in vivo. This review discusses how studies in systems pharmacology provided a deeper understanding of the safety and efficacy of existing medications and would be going to contribute to the drug development in the future. We cover the issues of hERG channel-targeting drugs and arrhythmias. Recently we have demonstrated that some of Class III antiarrhythmic agents have dual effect on hERG channel; these drugs not only block hERG current as generally defined but also facilitate the voltage-dependent activation so that it can increase hERG currents at low potentials close to the threshold for channel activation. Moreover, we also found that some of non-cardiac agents such as haloperidol and fluoxetine have facilitation effect on hERG channel. Therefore the clinical importance of hERG facilitation needs further characterization. We then discuss how the facilitation of hERG channel contributes IKr current and cardiac action potential. We propose that this mechanism prevents the excessive prolongation of APD and development of early afterdepolarization (EAD), one of the substrates for torsade de pointes induced by drugs, suggesting that the facilitation effect suppresses the proarrhythmia risk. Taken together, these types of analyses can lead to new therapeutic options while improving rational drug development and the safety assessment.

Inorganic phosphate (Pi) is an essential nutrient for several biological functions, including intracellular signal transduction, the production and function of cell membranes, and energy exchange. The maintenance of constant circulating levels of Pi depends on the coordinated activity of three major organs: the intestine, the kidney, and the bones. To achieve these functions, a transport system is required to transfer Pi across hydrophobic cell membranes. Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 are also regulators of Pi homeostasis, and recent studies have identified other factors that contribute to the maintenance of Pi homeostasis, including first phosphatonins [fibroblast growth factor (FGF) 23] originated from osteocytes established the concept of the bone-kidney axis. In this review, we discuss Pi homeostasis through several tissues.

Drug metabolizing enzymes are key molecules responsible for elimination of drug from the body. Inter- and intra-individual variability in activity of the drug metabolizing enzymes is a critical issue in clinical chemotherapy. Induction of drug metabolizing enzymes is regulated by ligand-activated transcription factors, i.e., nuclear receptors, and a cause of clinical drug-drug interaction. Concomitant use of inducers and victim drugs should be avoided in clinic depending on the degree of seriousness, while drug candidates that have enzyme inducing activity should be avoided in drug discovery and development. Therefore, prediction of these risks is strongly required. In this article, we discuss structure-activity relationship of interaction with nuclear receptors and in vitro-in vivo extrapolation of clinical drug-drug interactions.

It has been well recognized that transporters as well as metabolic enzymes are important as determinants of drug pharmacokinetics. One of the reasons is the accumulation of clinically-relevant transporter-mediated drug interaction cases. Since the substrate specificity of transporters is very broad as metabolic enzymes, substrate drugs are often recognized by multiple transporters and metabolic enzymes. Moreover, inhibitor drugs can sometimes simultaneously inhibit multiple molecules with different potencies. Under such situation, to understand the influence of altered functions of individual molecules on the efficiency of overall detoxification system of drugs, pharmacokinetic analysis using mathematical modeling is thought to be valuable. In this manuscript, the current status and challenges of the quantitative risk evaluation of drug interactions are briefly overviewed.

Many biological processes in mammals are subject to daily oscillations, and some of these are controlled by self-sustained oscillation mechanism called circadian clock. The rhythmic variations in biological functions also affect the efficacy and/or toxicity of drugs: the potency of a large number of drugs varies depending on the time of day when the drugs are administered. Circadian rhythms are controlled by a genetic feedback loops composed of clock genes. This mechanism interconnects the positive and negative limbs of circadian clockwork circuitry and also regulates 24-hr variation in output physiology through the periodic activation/repression of clock-controlled genes. The circadian-controlled output pathways include those that control the expression of many enzymes and regulators involved in xenobiotic detoxification, such as cytochrome P450 enzymes, carboxylesterases, and xenobiotic transporters. In addition to the intracellular molecular clock, circadian rhythms in cell physiology are also generated by extracellular factors. During the daily feeding cycle, the time-dependent accumulation of bile acids in the intestinal epithelial cells generates circadian changes in the expression of several types of transporter. This may also constitute a molecular clock-independent mechanism by which bile acid causes the circadian change in the intestinal absorption of drugs. This review presents an overview of regulation mechanism for circadian changes in the drug disposition and describes the importance of DDS development for rational chronopharmacotherapy.