The International Transporter Consortium (ITC) has recently described seven transporters of particular relevance to drug development. Based on the second ITC transporter workshop in 2012, we have identified additional transporters of emerging importance in pharmacokinetics, interference of drugs with transport of endogenous compounds, and drug-drug interactions (DDIs) in humans. The multidrug and toxin extrusion proteins (MATEs, gene symbol SLC47A) mediate excretion of organic cations into bile and urine. MATEs are important in renal DDIs. Multidrug resistance proteins (MRPs or ABCCs) are drug and conjugate efflux pumps, and impaired activity of MRP2 results in conjugated hyperbilirubinemia. The bile salt export pump (BSEP or ABCB11) prevents accumulation of toxic bile salt concentrations in hepatocytes, and BSEP inhibition or deficiency may cause cholestasis and liver injury. In addition, examples are presented on the roles of nucleoside and peptide transporters in drug targeting and disposition. This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG is providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.
Ethnicity is one factor that may account for the observed differences in both pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, resulting in variability in response to drug therapy. Given that the applicability of clinical study results to the treatment of an individual patient is a critical consideration in a physician's choice of drug therapy, drug development should seek to ensure that a clinical pharmacologic evaluation includes a population that is representative of the target therapeutic population. Ethnic diversity in drug response with respect to safety and efficacy and the resulting differences in recommended doses have been well described for some drugs. Some of these differential responses may be related to the pharmacogenomics of a particular drug. Pharmacogenomic techniques have recently enjoyed widespread use in studies of drug exposure and response. The clinical relevance of variability in drug response due to pharmacogenomics of drug-metabolizing enzymes was considered at a September 2004 workshop cosponsored by the US Food and Drug Administration (FDA), Johns Hopkins University, and the Pharmaceutical Research and Manufacturers of America (http://www.fda.gov/cder/Offices/OCPB/workshops.htm).
Race and ethnicity can contribute to interindividual differences in drug exposure and/or response, which may alter risk-benefit in certain populations. Approximately one-fifth of new drugs approved in the past 6 years demonstrated differences in exposure and/or response across racial/ethnic groups, translating to population-specific prescribing recommendations in a few cases. When data from diverse populations were lacking, additional postmarketing studies were recommended. In this review we highlight several cases where race/ethnicity was central to regulatory decision-making.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.