The Transport and Efflux of Glycosylated Luteinising Hormone-Releasing Hormone Analogues in Caco-2 Cell Model: Contributions of Glucose Transporters and Efflux Systems

Abstract Luteinising hormone-releasing hormone (LHRH) analogues have wide therapeutic applications in the treatment of prostate cancers and endocrine disorders. The structure of LHRH was modified using a glycosylation strategy to increase the permeability of the peptide across biological membranes. Lactose, galactose and glucose units were coupled to LHRH peptide, and the impact of glucose transporters, GLUT2 and SGLT1, was investigated in the transport of the analogues. Results showed the contribution of both transporters in the transport of all LHRH analogues. In the presence of glucose transporter inhibitors, reduction in the apparent permeability ( P app ) was greatest for compound 6, which contains a glucose unit in the middle of the sequence ( P app = 58.54 ± 4.72 cm/s decreased to P app = 1.6 ± 0.345 cm/s). The basolateral to apical flux of the glycosylated derivatives and the impact of two efflux pumps was also examined in Caco-2 cell monolayers. The efflux ratios (ERs) of all LHRH analogues in Caco-2 cells were in the range of 0.06–0.2 except for compound 4 ( galactose modified, ER=8.03). We demonstrated that the transport of the glycosylated peptides was facilitated through glucose transporters. The proportion of glucose and lactose derivatives pumped out by efflux pumps did not affect the P app values of the analogues.