title: The use of a dendrimer-propranolol prodrug to bypass efflux transporters and enhance oral bioavailability.
abstract: 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, P(app), of propranolol was increased and its B-->A P(app) 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 P(app) of propranolol conjugates was reduced in the presence of the endocytosis inhibitor colchicine and was lower at 4 degrees C than at 37 degrees C, suggesting that the enhancement mechanism involves endocytosis-mediated transepithelial transport. The A-->B P(app) 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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK. Antony@DEmanuele.net
authors.forename: Antony
authors.initials: A
authors.lastname: D'Emanuele
authors.forename: Rachaneekorn
authors.initials: R
authors.lastname: Jevprasesphant
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Penny
authors.forename: David
authors.initials: D
authors.lastname: Attwood
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000085:Acetates / Q000737:chemistry; D000284:Administration, Oral; D001682:Biological Availability; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003078:Colchicine / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004705:Endocytosis / Q000187:drug effects; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007848:Laurates / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry / Q000493:pharmacokinetics; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D011433:Propranolol / Q000138:chemical synthesis / Q000494:pharmacology*; D012995:Solubility / Q000187:drug effects; D013696:Temperature
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000085:Acetates; D004337:Drug Carriers; D007848:Laurates; D011073:Polyamines; D011355:Prodrugs; D016572:Cyclosporine; D011433:Propranolol; C045557:chloroacetyl chloride; D003078:Colchicine