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The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug-drug interactions.
Cancer Chemother Pharmacol. 2014 Apr; 73(4):869-74.CC

Abstract

PURPOSE

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.

METHOD

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+Show Affiliations

DMPK Laboratories, Celgene Corporation, Summit, NJ, USA, ztong@celgene.com.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24627218

Citation

Tong, Zeen, et al. "The Interactions of Lenalidomide With Human Uptake and Efflux Transporters and UDP-glucuronosyltransferase 1A1: Lack of Potential for Drug-drug Interactions." Cancer Chemotherapy and Pharmacology, vol. 73, no. 4, 2014, pp. 869-74.
Tong Z, Yerramilli U, Surapaneni S, et al. The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug-drug interactions. Cancer Chemother Pharmacol. 2014;73(4):869-74.
Tong, Z., Yerramilli, U., Surapaneni, S., & Kumar, G. (2014). The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug-drug interactions. Cancer Chemotherapy and Pharmacology, 73(4), 869-74. https://doi.org/10.1007/s00280-014-2415-y
Tong Z, et al. The Interactions of Lenalidomide With Human Uptake and Efflux Transporters and UDP-glucuronosyltransferase 1A1: Lack of Potential for Drug-drug Interactions. Cancer Chemother Pharmacol. 2014;73(4):869-74. PubMed PMID: 24627218.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug-drug interactions. AU - Tong,Zeen, AU - Yerramilli,Usha, AU - Surapaneni,Sekhar, AU - Kumar,Gondi, Y1 - 2014/03/14/ PY - 2014/01/21/received PY - 2014/02/12/accepted PY - 2014/3/15/entrez PY - 2014/3/15/pubmed PY - 2014/7/16/medline SP - 869 EP - 74 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother. Pharmacol. VL - 73 IS - 4 N2 - PURPOSE: 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. METHOD: 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. SN - 1432-0843 UR - https://www.unboundmedicine.com/medline/citation/24627218/The_interactions_of_lenalidomide_with_human_uptake_and_efflux_transporters_and_UDP_glucuronosyltransferase_1A1:_lack_of_potential_for_drug_drug_interactions_ L2 - https://dx.doi.org/10.1007/s00280-014-2415-y DB - PRIME DP - Unbound Medicine ER -