title: The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug-drug interactions.
abstract: OBJECTIVE
  Lenalidomide is an immunomodulatory agent used for the treatment of myelodysplastic syndromes and multiple myeloma. Renal clearance of lenalidomide is the predominant elimination route and is approximately twofold greater than the glomerular filtration rate (GFR), suggesting the potential contribution of an active secretory mechanism. In vitro studies were conducted to examine whether lenalidomide is a substrate of drug transporters, namely P-glycoprotein (P-gp), human breast cancer resistance protein (BCRP), multidrug resistance proteins (MRP1, MRP2, MRP3), organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1 and OCT2), human organic cation transporter novel 1 and 2 (OCTN1 and OCTN2), multidrug and toxin extrusion (MATE1) and organic anion transporting polypeptide (OATP1B1). Lenalidomide was also evaluated as an inhibitor of P-gp, BCRP, MRP2, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 and bile salt export pump (BSEP). In addition, inhibition of UDP-glucuronosyltransferase 1A1 (UGT1A1) variants by lenalidomide was also assessed.
  
  
  METHODS
  Cells or vesicles expressing each of the human transporters were used for uptake and inhibition studies, with appropriate probe substrates and known inhibitors.
  
  
  RESULTS
  Results of these studies indicate that the lenalidomide is not a substrate for the transporters examined, except that it is weak substrate of P-gp. None of the transporters studied were inhibited by lenalidomide. Lenalidomide is not an inhibitor of UGT1A1*1/*1 or its polymorphic variants UGT1A1*1/*28 and UGT1A1*28/*28.
  
  
  CONCLUSIONS
  Drug interactions are unlikely to occur when lenalidomide is co-administered with substrates or inhibitors of these transporters. In addition, lenalidomide is unlikely to cause interactions when co-administered with substrates of UGT1A1.
authors.affiliation: DMPK Laboratories, Celgene Corporation, Summit, NJ, USA, ztong@celgene.com.
authors.forename: Zeen
authors.initials: Z
authors.lastname: Tong
authors.forename: Usha
authors.initials: U
authors.lastname: Yerramilli
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
authors.forename: Gondi
authors.initials: G
authors.lastname: Kumar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D004347:Drug Interactions; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D000077269:Lenalidomide; D026901:Membrane Transport Proteins / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000099148:UGT1A1 Enzyme
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D020533:Angiogenesis Inhibitors; D014453:Glucuronosyltransferase; D000077269:Lenalidomide; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D013792:Thalidomide; D000099148:UGT1A1 Enzyme; C116614:ABCG2 protein, human