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Preface: Molecular Mechanisms, Novel Modes of Regulation, and Therapeutic Strategies
Advanced Drug Delivery Reviews 116 (2017) 1–2
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr
Preface
Preface: Molecular Mechanisms, Novel Modes of Regulation, and Therapeutic Strategies
Drug transporters are the gatekeepers for cells in many organs such as brain, liver, intestine, kidney, and placenta, controlling the flux of drugs into and out of the cells, and therefore crucially influence the absorption, distribution and elimination of drugs in the body. Major drug transporters can be classified into two superfamilies. One superfamily is the Solute Carrier Transporters (SLCs), which mediate drug uptake into the cells. The other superfamily is the ATP-Binding Cassette Transporters (ABCs), which are responsible for moving drugs out of the cells. For the past couple of years, there has been significant advances in the drug transport field: the identification of new structural motives critical for the function of the transporters, the discovery of new regulatory pathways, the establishment of sophisticated techniques for validating transport process, all of which lead to a better understanding of the physiological roles and clinical implications of these transporters. The articles featured in this theme issue, contributed by experts in the drug transport field, reflect these advances. Understanding the roles drug transporters play in drug disposition will provide significant insights into the future design of strategies aimed at maximizing therapeutic efficacy and minimizing drug-related toxicity. In this issue, Hong described the development made in identifying the critical amino acids, and domains in the drug transporters that are important for the function of the transporters. These amino acids and domains play significant roles in the interaction of the transporters with their substrates and with other regulatory proteins, in the expression of the transporters, and in serving as acceptors for posttranslational modifications. Due to the difficulty to obtain the crystal structures for most of the membrane proteins, biochemical approaches such as site-directed mutagenesis, deletion or truncation of the transporter fragments, combined with computer modeling were used to delineate the transport mechanisms and the structure-function relationship of drug transporters. The expression and function of the drug transporters are influenced by a range of factors. One of them is the variations in the genes encoding these transporters in an individual or among a group of individuals. Such variations can occur within the coding regions or non-coding regions and contribute to the inter-individual’s variability in their response to drug therapy and toxicity. Zhou et al. highlighted the progress in identification of the genetic variations in several key drug transporters of SLC family and ABC family as well as impact of these genetic variations on drug pharmacokinetics and pharmacodynamics. These works can provide very useful insights into the development of diseases, drug response, and drug toxicities. In addition to the genetic factor, the expression and function of the drug transporters are also influenced by loops and layers of post-
http://dx.doi.org/10.1016/j.addr.2017.08.008 0169-409X/© 2017 Published by Elsevier B.V.
translational modifications. Post-translational modification is a process where the amino acid side chains in a target protein are modified by conjugating new functional group(s) through reversible or irreversible biochemical reactions. Post-translational modification affects the folding, conformation, distribution, trafficking, stability, and activity of the drug transporters. The significant contribution of post-translational modification to transporter-mediated drug disposition in the body is discussed in the review contributed by Xu et al. The characteristic of many drug transporters is their interaction with strikingly diverse range of compounds including drugs, environmental toxins, and food supplements. As a result, the interactions between drug and the various other compounds can happen at the transporter molecules and influence drug availability and therapeutic efficacy. Li et al. described the detailed effects of dietary and herbal phytochemicals on drug transporters. These phytochemicals can act as the substrates or inhibitors of the drug transporters and as modulators that affect the expression and activity of the drug transporters. These interactions should be taken into consideration when predicting the clinical outcome of the drugs. Drug transporters are mainly expressed in the kidney, liver, brain and placenta. The dysfunction of transporters in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Al-Enazy et al. provided an overview on placental structure and function, and various mechanisms involved in placental transport of drugs, focusing on several placental transporters and drug metabolizing enzymes. As placenta serves as the interface between mother and her fetus during pregnancy, understanding these issues will guide the choice of therapeutics and approaches appropriate for treating diseases and protecting fetus during the pregnancy. George et al. dedicated their review to the impact of the expression and function of drug transporters in the kidney on the accumulation of nephrotoxicants (both environmental chemicals and pharmaceutics) in the proximal tubule cells and the toxicant-induced kidney injury. During the early phase of drug discovery, optimization of the disposition profiles through accurately predicting clearance mechanism is a crucial step for quicker, resource saving, and more predictable drug development. Varma et al., discussed strategies in this regard with the application of the framework on transporter-mediated clearance mechanism - Extended Clearance Classification System and ligand-based modeling approaches (SAR/QSAR models). The focus was placed on the transporter-mediated drug transport in liver and kidney. These strategies contributed to the reduction of the attrition rate of a drug candidate. Another important consideration during drug development is the interaction between drug and transporters. The investigative drug can
2
Preface
either act as a substrate or inhibitor of one or more transporters thereby affecting transporter-mediated disposition of other drugs. The review by Lee et al., discussed, from a regulatory science perspective, the various criteria set by FDA in evaluating transporter-mediated drug-drug interaction so that appropriate measure can be taken to alleviate drug toxicity and enhance efficacy. In conclusion, this theme issue offers both wide scope and depth of the present status of the investigations on transporter-mediated drug disposition. We would like to thank all the authors for their time and
efforts to contribute to this frontier information, which will be useful to investigators engaged with this exciting and rapidly growing field. Guofeng You Department of Pharmaceutics, Rutgers University, Piscataway, NJ, USA 08854
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr
Preface
Preface: Molecular Mechanisms, Novel Modes of Regulation, and Therapeutic Strategies
Drug transporters are the gatekeepers for cells in many organs such as brain, liver, intestine, kidney, and placenta, controlling the flux of drugs into and out of the cells, and therefore crucially influence the absorption, distribution and elimination of drugs in the body. Major drug transporters can be classified into two superfamilies. One superfamily is the Solute Carrier Transporters (SLCs), which mediate drug uptake into the cells. The other superfamily is the ATP-Binding Cassette Transporters (ABCs), which are responsible for moving drugs out of the cells. For the past couple of years, there has been significant advances in the drug transport field: the identification of new structural motives critical for the function of the transporters, the discovery of new regulatory pathways, the establishment of sophisticated techniques for validating transport process, all of which lead to a better understanding of the physiological roles and clinical implications of these transporters. The articles featured in this theme issue, contributed by experts in the drug transport field, reflect these advances. Understanding the roles drug transporters play in drug disposition will provide significant insights into the future design of strategies aimed at maximizing therapeutic efficacy and minimizing drug-related toxicity. In this issue, Hong described the development made in identifying the critical amino acids, and domains in the drug transporters that are important for the function of the transporters. These amino acids and domains play significant roles in the interaction of the transporters with their substrates and with other regulatory proteins, in the expression of the transporters, and in serving as acceptors for posttranslational modifications. Due to the difficulty to obtain the crystal structures for most of the membrane proteins, biochemical approaches such as site-directed mutagenesis, deletion or truncation of the transporter fragments, combined with computer modeling were used to delineate the transport mechanisms and the structure-function relationship of drug transporters. The expression and function of the drug transporters are influenced by a range of factors. One of them is the variations in the genes encoding these transporters in an individual or among a group of individuals. Such variations can occur within the coding regions or non-coding regions and contribute to the inter-individual’s variability in their response to drug therapy and toxicity. Zhou et al. highlighted the progress in identification of the genetic variations in several key drug transporters of SLC family and ABC family as well as impact of these genetic variations on drug pharmacokinetics and pharmacodynamics. These works can provide very useful insights into the development of diseases, drug response, and drug toxicities. In addition to the genetic factor, the expression and function of the drug transporters are also influenced by loops and layers of post-
http://dx.doi.org/10.1016/j.addr.2017.08.008 0169-409X/© 2017 Published by Elsevier B.V.
translational modifications. Post-translational modification is a process where the amino acid side chains in a target protein are modified by conjugating new functional group(s) through reversible or irreversible biochemical reactions. Post-translational modification affects the folding, conformation, distribution, trafficking, stability, and activity of the drug transporters. The significant contribution of post-translational modification to transporter-mediated drug disposition in the body is discussed in the review contributed by Xu et al. The characteristic of many drug transporters is their interaction with strikingly diverse range of compounds including drugs, environmental toxins, and food supplements. As a result, the interactions between drug and the various other compounds can happen at the transporter molecules and influence drug availability and therapeutic efficacy. Li et al. described the detailed effects of dietary and herbal phytochemicals on drug transporters. These phytochemicals can act as the substrates or inhibitors of the drug transporters and as modulators that affect the expression and activity of the drug transporters. These interactions should be taken into consideration when predicting the clinical outcome of the drugs. Drug transporters are mainly expressed in the kidney, liver, brain and placenta. The dysfunction of transporters in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Al-Enazy et al. provided an overview on placental structure and function, and various mechanisms involved in placental transport of drugs, focusing on several placental transporters and drug metabolizing enzymes. As placenta serves as the interface between mother and her fetus during pregnancy, understanding these issues will guide the choice of therapeutics and approaches appropriate for treating diseases and protecting fetus during the pregnancy. George et al. dedicated their review to the impact of the expression and function of drug transporters in the kidney on the accumulation of nephrotoxicants (both environmental chemicals and pharmaceutics) in the proximal tubule cells and the toxicant-induced kidney injury. During the early phase of drug discovery, optimization of the disposition profiles through accurately predicting clearance mechanism is a crucial step for quicker, resource saving, and more predictable drug development. Varma et al., discussed strategies in this regard with the application of the framework on transporter-mediated clearance mechanism - Extended Clearance Classification System and ligand-based modeling approaches (SAR/QSAR models). The focus was placed on the transporter-mediated drug transport in liver and kidney. These strategies contributed to the reduction of the attrition rate of a drug candidate. Another important consideration during drug development is the interaction between drug and transporters. The investigative drug can
2
Preface
either act as a substrate or inhibitor of one or more transporters thereby affecting transporter-mediated disposition of other drugs. The review by Lee et al., discussed, from a regulatory science perspective, the various criteria set by FDA in evaluating transporter-mediated drug-drug interaction so that appropriate measure can be taken to alleviate drug toxicity and enhance efficacy. In conclusion, this theme issue offers both wide scope and depth of the present status of the investigations on transporter-mediated drug disposition. We would like to thank all the authors for their time and
efforts to contribute to this frontier information, which will be useful to investigators engaged with this exciting and rapidly growing field. Guofeng You Department of Pharmaceutics, Rutgers University, Piscataway, NJ, USA 08854