PMID- 19264104
OWN - NLM
STAT- MEDLINE
DCOM- 20090819
LR  - 20161125
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Linking)
VI  - 137
IP  - 1
DP  - 2009 Jul 1
TI  - Quasi-equilibrium analysis of the ion-pair mediated membrane transport of 
      low-permeability drugs.
PG  - 31-7
LID - 10.1016/j.jconrel.2009.02.018 [doi]
AB  - The aim of this research was to gain a mechanistic understanding of ion-pair 
      mediated membrane transport of low-permeability drugs. Quasi-equilibrium mass 
      transport analyses were developed to describe the ion-pair mediated 
      octanol-buffer partitioning and hydrophobic membrane permeation of the model 
      basic drug phenformin. Three lipophilic counterions were employed: 
      p-toluenesulfonic acid, 2-naphthalenesulfonic acid, and 1-hydroxy-2-naphthoic 
      acid (HNAP). Association constants and intrinsic octanol-buffer partition 
      coefficients (Log P(AB)) of the ion-pairs were obtained by fitting a transport 
      model to double reciprocal plots of apparent octanol-buffer distribution 
      coefficients versus counterion concentration. All three counterions enhanced the 
      lipophilicity of phenformin, with HNAP providing the greatest increase in Log 
      P(AB), 3.7 units over phenformin alone. HNAP also enhanced the apparent membrane 
      permeability of phenformin, 27-fold in the PAMPA model, and 4.9-fold across 
      Caco-2 cell monolayers. As predicted from a quasi-equilibrium analysis of 
      ion-pair mediated membrane transport, an order of magnitude increase in 
      phenformin flux was observed per log increase in counterion concentration, such 
      that log-log plots of phenformin flux versus HNAP concentration gave linear 
      relationships. These results provide increased understanding of the underlying 
      mechanisms of ion-pair mediated membrane transport, emphasizing the potential of 
      this approach to enable oral delivery of low-permeability drugs.
FAU - Miller, Jonathan M
AU  - Miller JM
AD  - Center for Molecular Drug Targeting, Department of Pharmaceutical Sciences, 
      College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
FAU - Dahan, Arik
AU  - Dahan A
FAU - Gupta, Deepak
AU  - Gupta D
FAU - Varghese, Sheeba
AU  - Varghese S
FAU - Amidon, Gordon L
AU  - Amidon GL
LA  - eng
PT  - Journal Article
DEP - 20090302
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Benzenesulfonates)
RN  - 0 (Buffers)
RN  - 0 (Ions)
RN  - 0 (Membranes, Artificial)
RN  - 0 (Naphthalenesulfonates)
RN  - 0 (Naphthols)
RN  - 0 (Octanols)
RN  - 0 (Pharmaceutical Preparations)
RN  - DD5K7529CE (Phenformin)
RN  - O9S4K2S25E (2-naphthalenesulfonic acid)
RN  - QGV5ZG5741 (4-toluenesulfonic acid)
RN  - U8LZ3R07L8 (1-hydroxy-2-naphthoic acid)
SB  - IM
MH  - Benzenesulfonates/chemistry/metabolism
MH  - Biological Transport/drug effects
MH  - Buffers
MH  - Caco-2 Cells
MH  - Cell Membrane Permeability/*drug effects
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Hydrophobic and Hydrophilic Interactions
MH  - Ions/*metabolism
MH  - Membranes, Artificial
MH  - Molecular Structure
MH  - Naphthalenesulfonates/chemistry/metabolism
MH  - Naphthols/chemistry/metabolism
MH  - Octanols/metabolism
MH  - Permeability/drug effects
MH  - Pharmaceutical Preparations/*chemistry/*metabolism
MH  - Phenformin/chemistry/*metabolism
EDAT- 2009/03/07 09:00
MHDA- 2009/08/20 09:00
CRDT- 2009/03/07 09:00
PHST- 2009/02/16 00:00 [received]
PHST- 2009/02/20 00:00 [accepted]
PHST- 2009/03/07 09:00 [entrez]
PHST- 2009/03/07 09:00 [pubmed]
PHST- 2009/08/20 09:00 [medline]
AID - S0168-3659(09)00129-1 [pii]
AID - 10.1016/j.jconrel.2009.02.018 [doi]
PST - ppublish
SO  - J Control Release. 2009 Jul 1;137(1):31-7. doi: 10.1016/j.jconrel.2009.02.018. 
      Epub 2009 Mar 2.