Transporters are increasingly recognized as important processes in drug disposition. More recently, functional characterization of drug uptake transporters has revealed that a family of drug uptake transporters known as the Organic Anion Transporting Polypeptides (OATPs), are critical to the cellular uptake of drugs into organs such as the liver, intestine, and brain. Studies have revealed that certain human OATPs such as OATP-C and OATP-8 may be the key hepatic drug uptake transporters, while OATP-A expression at the level of the blood brain barrier may be responsible for the CNS entry of certain drugs. We are now able to show that OATP-A is expressed in the small intestines, and may be a key transporter responsible enhancing the gastrointestinal absorption of various drugs in clinical use. It is our hypothesis that intersubject variability in the expressed level and activity of OATP transporters affects drug disposition and responsiveness. However, the extent of our knowledge regarding human OATP transporters is limited. Studies carried out from this laboratory have identified a number of single nucleotide polymorphisms (SNPs) in OATP transporters importantly associated with drug disposition and response. Accordingly, in this application, studies on the role of genetic variability in certain human OATP transporters to transporter function, both in vitro and in vivo, are outlined.
Specific Aim 1 is focused studies on the in vitro functional characterization of allelic variants newly identified by this laboratory in OATP-A, OATP-8 and OATP-C.
In Specific Aim 2, to better understand the interplay between OATP-mediated drug uptake versus P-glycoprotein (MDR1) or MRP2 (cMOAT)-mediated drug efflux, studies are proposed on the creation of model cell lines expressing an OATP transporter along with P-glycoprotein or MRP2, in combinations reflective of organs such as the liver, intestine and brain.
In Specific Aim 3, the role of commonly occurring SNPs in OATP-C, which studies from this laboratory had shown to be functionally significant in vitro, will be tested in human subjects using the well-known OATP-C-specific substrate, pravastatin, and a newly identified substrate, rifampin, as in vivo probes for this transporter. Moreover, variability in the extent of rifampin-mediated induction of the drug metabolizing enzyme, CYP3A, among subjects with variant OATP-C alleles, will also be tested. ? ?
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| Ho, Richard H; Leake, Brenda F; Urquhart, Brad L et al. (2011) Functional characterization of genetic variants in the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). J Gastroenterol Hepatol 26:1740-8 |
| Ho, Richard H; Leake, Brenda F; Kilkenny, Dawn M et al. (2010) Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics 20:45-57 |
| Zaher, Hani; zu Schwabedissen, Henriette E Meyer; Tirona, Rommel G et al. (2008) Targeted disruption of murine organic anion-transporting polypeptide 1b2 (Oatp1b2/Slco1b2) significantly alters disposition of prototypical drug substrates pravastatin and rifampin. Mol Pharmacol 74:320-9 |
