The use of a dendrimer-propranolol prodrug to bypass efflux transporters and enhance oral bioavailability

The aim of the study was to determine the effects on the transport of propranolol across monolayers of the human colon adenocarcinoma cell line, Caco-2, of forming a prodrug by conjugating to generation 3 (G3) and lauroyl-G3 PAMAM dendrimers. Propranolol is a poorly soluble drug and known substrate of the P-glycoprotein (P-gp) efflux transporter. Propranolol-G3 dendrimer conjugates were synthesised by surface attachment of two, four or six propranolol molecules. The apical (A) to basolateral (B) apparent permeability coefficient, Papp, of propranolol was increased and its B→A Papp decreased following conjugation to G3 dendrimers. Conjugation of propranolol to lauroyl-G3 dendrimers further increased its A→B P app. Our findings show that the A→B Papp of propranolol conjugates was reduced in the presence of the endocytosis inhibitor colchicine and was lower at 4°C than at 37°C, suggesting that the enhancement mechanism involves endocytosis-mediated transepithelial transport. The A→B Papp of conjugated propranolol was not altered in the presence of the P-gp inhibitor cyclosporin A suggesting that conjugation of drug to dendrimer allows the bypassing of the efflux transporter. The results suggest that dendrimer-drug prodrugs may be used to increase drug solubility and bypass drug efflux transporters, therefore increasing drug bioavailability. © 2004 Elsevier B.V. All rights reserved