Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology.
Our understanding of the mechanisms behind inter- and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient- and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender.
VanWert
Adam L
AL
Department of Pharmaceutical Sciences, Wilkes University, Wilkes-Barre, PA 18766, USA.
Gionfriddo
Michael R
MR
Sweet
Douglas H
DH
D002352:Carrier Proteins / Q000378:metabolism; D016764:Cell Polarity; D004848:Epithelium / Q000378:metabolism*; D016166:Free Radical Scavengers; D006801:Humans; D015394:Molecular Structure; D027361:Organic Anion Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
D002352:Carrier Proteins; D016166:Free Radical Scavengers; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins