The second in a pair of articles on drug transporters, this article focuses on uptake transporters that actively pump drugs into cells.
Drs. Horn and Hansten are both professorsof pharmacy at the University ofWashington School of Pharmacy. Foran electronic version of this article,including references if any, visitwww.hanstenandhorn.com.
In the first article on drug transporters,we focused on the effluxtransporter P-glycoprotein (December2008 Pharmacy Times; seewww.PharmacyTimes.com/DrugTransporters). This time we are going toexamine the uptake transporters. Thesetransporters actively pump drugs intocells, including hepatocytes and renaltubular cells. Drugs can then be secretedinto the bile, metabolized (hepatocyte),or secreted into the urine (renal tubularcell). These uptake transporters aregenerally divided into those that transportanionic molecules (organic aniontransporters [OATs] or organic aniontransporting polypeptides [OATPs]) andthose that transport cationic molecules(organic cation transporters [OCTs]).OATPs are primarily found in the liver,while OATs and OCTs can be found inthe liver, kidney, and brain.
Examples of OAT substrates includemethotrexate and nonsteroidal antiinflammatorydrugs (NSAIDs). Thesedrugs are secreted by the renal tubularcells as their primary method ofelimination. When 2 drugs that are bothsubstrates for the same OAT are coadministered,the possibility for competitiveinhibition of the transporter, andhence of drug elimination, will be present.Numerous reports have describedan interaction between NSAIDs andmethotrexate that can result in severemethotrexate toxicity. This outcome isthe result of the NSAID competing forOATs and reducing the renal clearanceof methotrexate.1 Several HMG-CoAreductase inhibitors including pravastatinand cerivastatin are partially eliminatedby OATs. Cyclosporine is an inhibitorof OAT and has been demonstrated toincrease the plasma concentrations ofthese statins by over 5-fold.2,3 The abilityof probenecid to reduce the renal clearanceof penicillins and cephalosporins isat least partially due to competition forOATs in the renal tubule.4
OCTs transport a number of drugsincluding cimetidine, metformin, procainamide,and triamterene from theplasma into hepatocytes and renal tubularcells. As with cytochromes, a varietyof different OAT and OCT transportersexist. Metformin's uptake into the liver,where it exerts its pharmacologic effect,is mediated by OCT1, while its eliminationvia the kidney is primarily due toOCT2. The capacity of OCT2 to transportmetformin is at least 10 times greaterthan OCT1. Thus, OTC2 and the renalelimination of metformin are primarilyresponsible for its pharmacologic properties.5 Cimetidine also is a substratefor OCT and can compete with metforminfor both OCT1 and OCT2. BecauseOCT2 is primarily responsible for metformin'selimination, competition fromcimetidine will result in reduced renalclearance of metformin and elevatedplasma concentrations.6,7 Procainamideis another known OCT substrate. Itsrenal clearance has been reduced followingcoadministration with severaldrugs, including amiodarone,8 levofloxacin,9 and cimetidine.10
The clinical outcome of drug interactionsbased on OAT or OCT inhibitionwill depend on the pharmacologic propertiesof the object drug. For example,inhibiting the hepatic uptake of a drugmay reduce its metabolism, leading tohigher plasma concentrations. If thesite of action of the object drug is intrahepatic(eg, HMG-CoA reductase inhibitorsor oral hypoglycemic drugs), however,a reduction in the desired pharmacologiceffect also may occur, despiteincreased plasma concentrations.
Nevertheless, the resulting increasein the drug's plasma concentration maylead to an increase in side effects unrelatedto the drug's therapeutic effect.Relating to the examples given above,patients taking statins might have anincreased risk of myopathy, whereasthose on metformin could have a greaterrisk of developing lactic acidosis.The effect of inhibited object drug renalclearance will depend on the percent ofdrug eliminated via the kidney and itstherapeutic window. In general, clinicallysignificant effects will occur withdrugs having at least 50% of their eliminationvia renal secretion and demonstratea narrow therapeutic window.
Finally, although a large number ofdrugs have been shown in vitro to bepotential inhibitors of OAT and OCT,their concentrations in vivo are oftentoo low to produce significant competitionfor transport with other drugs.