title: pH Dependent but not P-gp Dependent Bidirectional Transport Study of S-propranolol: The Importance of Passive Diffusion.
abstract: OBJECTIVE
  Recent controversial publications, citing studies purporting to show that P-gp mediates the transport of propranolol, proposed that passive biological membrane transport is negligible. Based on the BDDCS, the extensively metabolized-highly permeable-highly soluble BDDCS class 1 drug, propranolol, shows a high passive permeability at concentrations unrestricted by solubility that can overwhelm any potential transporter effects. Here we reinvestigate the effects of passive diffusion and carrier-mediated transport on S-propranolol.
  
  
  METHODS
  Bidirectional permeability and inhibition of efflux transport studies were carried out in MDCK, MDCK-MDR1 and Caco-2 cell lines at different concentrations. Transcellular permeability studies were conducted at different apical pHs in the rat jejunum Ussing chamber model and PAMPA system.
  
  
  RESULTS
  S-propranolol exhibited efflux ratios lower than 1 in MDCK, MDCK-MDR1 and Caco-2 cells. No significant differences of Papp, B->A in the presence and absence of the efflux inhibitor GG918 were observed. However, an efflux ratio of 3.63 was found at apical pH 6.5 with significant decrease in Papp, A->B and increase in Papp, B->A compared to apical pH 7.4 in Caco-2 cell lines. The pH dependent permeability was confirmed in the Ussing chamber model. S-propranolol flux was unchanged during inhibition by verapamil and rifampin. Furthermore, pH dependent permeability was also observed in the PAMPA system.
  
  
  CONCLUSIONS
  S-propranolol does not exhibit active transport as proposed previously. The "false" positive efflux ratio can be explained by the pH partition theory. As expected, passive diffusion, but not active transport, plays the primary role in the permeability of the BDDCS class 1 drug propranolol.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, #24 Tongjiaxiang, Mailbox 210, Nanjing, 210009, Jiangsu, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Leslie Z
authors.initials: LZ
authors.lastname: Benet
authors.forename: Hideaki
authors.initials: H
authors.lastname: Okochi
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004058:Diffusion; D004285:Dogs; D004347:Drug Interactions; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007917:Leprostatic Agents / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D010539:Permeability; D011433:Propranolol / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000494:pharmacology; D013237:Stereoisomerism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D007917:Leprostatic Agents; D011433:Propranolol; D014700:Verapamil; D012293:Rifampin