title: The application of P-gp inhibiting phospholipids as novel oral bioavailability enhancers - An in vitro and in vivo comparison.
abstract: The efflux transporter P-glycoprotein (P-gp) significantly modulates drug transport across the intestinal mucosa, strongly reducing the systemic absorption of various active pharmaceutical ingredients. P-gp inhibitors could serve as helpful tools to enhance the oral bioavailability of those substances. As a membrane-associated protein P-gp is surrounded and influenced by phospholipids. Some synthetic phospholipids have been found to strongly reduce P-gp's activity. In this study two representative phospholipids, 1,2-dioctanoyl-sn-glycero-3-phosphocholine (8:0 PC) and 1,2-didecanoyl-sn-glycero-3-phosphocholine (10:0 PC), were compared with Tween® 80 and Cremophor® EL, both commonly used surfactants with P-gp inhibitory properties. Their influence on the cellular transport of the P-gp substrate rhodamine 123 (RH123) was examined using Caco-2 cell layers. In addition, fluorescence anisotropy measurements were performed in order to investigate their effect on membrane fluidity. Finally, we compared the phospholipids with Tween® 80 and the competitive P-gp inhibitor verapamil in an in vivo study, testing their effects on the oral bioavailability of the P-gp substrate drug ritonavir. Both phospholipids not only led to the strongest absorption of RH123, but a permeability enhancing effect was detected in addition to the P-gp inhibition. Their effects on membrane fluidity were not consistent with their P-gp inhibiting effects, and therefore suggested a more complex mode of action. Both phospholipids significantly increased the area under the ritonavir plasma level curve (AUC) within 150min by more than tenfold, but were inferior to Tween® 80, which showed superior solubilizing effects. Finally, these phospholipids represent a novel substance class showing a high permeabilization potential for P-gp substrates. Because of their physiological structure and intestinal degradability, good tolerability without systemic absorption is expected. Formulating P-gp substrates with an originally low oral bioavailability is a difficult task, requiring concerted interplay of all excipients. P-gp inhibiting phospholipids offer a new tool to help cope with these challenges.
authors: Department of Pharmaceutical Technology and Biopharmacy, Albert Ludwig University Freiburg, Hermann-Herder-Str. 9, D-79104 Freiburg, Germany. Electronic address: manuel.weinheimer@pharmazie.uni-freiburg.de.
authors: Manuel
authors: M
authors: Weinheimer
authors: Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuheimer Feld 329, D-69120 Heidelberg, Germany. Electronic address: gert.fricker@uni-hd.de.
authors: Gert
authors: G
authors: Fricker
authors: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany. Electronic address: juergen.burhenne@med.uni-heidelberg.de.
authors: Jürgen
authors: J
authors: Burhenne
authors: Department of Pharmaceutical Technology and Biopharmacy, Albert Ludwig University Freiburg, Hermann-Herder-Str. 9, D-79104 Freiburg, Germany.
authors: Patricia
authors: P
authors: Mylius
authors: Department of Pharmaceutical Technology and Biopharmacy, Albert Ludwig University Freiburg, Hermann-Herder-Str. 9, D-79104 Freiburg, Germany. Electronic address: rolf.schubert@pharmazie.uni-freiburg.de.
authors: Rolf
authors: R
authors: Schubert
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D016503:Drug Delivery Systems; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D010713:Phosphatidylcholines / Q000737:chemistry / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry / Q000494:pharmacology*; D011136:Polysorbates / Q000737:chemistry / Q000494:pharmacology; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000737:chemistry; D019438:Ritonavir / Q000493:pharmacokinetics*; D013501:Surface-Active Agents / Q000737:chemistry / Q000494:pharmacology; D014700:Verapamil / Q000737:chemistry / Q000494:pharmacology
chemical_list: C111346:1,2-dioctanoyl-sn-glycero-3-phosphocholine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010713:Phosphatidylcholines; D010743:Phospholipids; D011136:Polysorbates; D013501:Surface-Active Agents; D020112:Rhodamine 123; D014700:Verapamil; D019438:Ritonavir
keywords: 1,2-Didecanoyl-sn-glycero-3-phosphocholine (10:0 PC); 1,2-Didecanoyl-sn-glycero-3-phosphocholine (10:0 PC) (PubChem CID: 166886); 1,2-Dioctanoyl-sn-glycero-3-phosphocholine (8:0 PC); 1,2-Dioctanoyl-sn-glycero-3-phosphocholine (8:0 PC) (PubChem CID: 24779244); 1,6-Diphenyl-1,3,5-hexatriene (PubChem CID: 5376733); Caco-2; Oral drug delivery; P-glycoprotein; Polyethoxylated (35) castor oil (Cremophor® EL) (PubChem CID: Not found); Polyoxyethylene (20) sorbitan monooleate (Tween® 80) (PubChem CID: 86289060); Rhodamine 123 (PubChem CID: 65217); Ritonavir; Ritonavir (PubChem CID: 392622); Surfactants; Verapamil hydrochloride (PubChem CID: 62969)