J. Van Gelder et al., Evaluation of the potential of ion pair formation to improve the oral absorption of two potent antiviral compounds, AMD3100 and PMPA, INT J PHARM, 186(2), 1999, pp. 127-136
9-(2-phosphonyomethoxypropyl)adenine (PMPA) and AMD3100 are highly potent a
nd selective antiretroviral agents. Since PMPA is negatively charged and AM
D3100 positively charged at physiological pH, their transepithelial transpo
rt and their potential for oral drug delivery is very low. In this study, i
on pair formation was evaluated as a possible strategy to enhance transepit
helial transport of PMPA and AMD3100. Positively charged counter ions such
as t-hexyl-, t-heptyl-, t-octylammonium bromide and dodecyl-, tetradecyl-,
hexadecyltrimethylammonium bromide were used to form ion pairs with PMPA, w
hile sodium taurodeoxycholate (in vitro experiments) and sodium taurocholat
e (in vivo experiments) were used as counter ions for AMD3100. The effect o
f counter ions on transepithelial transport-of PMPA (1 mM) and AMD3100 (1 m
M) was investigated by measuring the flux across Caco-2 monolayers. An enha
ncement in drug transport could be observed at a concentration of 2 mM of h
exadecyltrimethylammonium bromide (counter ion for PMPA) and 10 mM of sodiu
m taurodeoxycholate (counter ion for AMD3100), but at the concentrations us
ed, the absorption enhancing effect could be attributed to a reduction of t
he integrity of the monolayers. When AMD3100 transport was tested at a conc
entration of 200 mu M, no Aux was observed, even in the presence of relativ
ely high concentrations of counter ion (20 times the concentration of AMD31
00). Results obtained from partitioning studies of the drugs in the presenc
e or absence of counter ion revealed that competition by other ions was res
ponsible for the absence of an effect: when pure water was used as the aque
ous phase, a reduction up to 24.4 +/- 1.4% and 17.0 +/- 1.3% of the initial
aqueous concentration was observed for PMPA and AMD3100, respectively; how
ever, as soon as other ions were present in the aqueous phase, the effect o
f the counter ion was diminished (25-50 mOsm) or completely abolished (270-
305 mOsm), The absorption enhancing effect of counter ions was also studied
in vivo: pharmacokinetic studies in rabbits showed that the oral bioavaila
bility of AMD3100 in the presence of 4 equivalents of taurocholic acid rema
ined very low and was only 3.2-fold better (i.e. 3.6%) in comparison to pur
e AMD3100. In view of the results obtained in the Caco-2, system, this abso
rption enhancement can be attributed to an effect on monolayer integrity ra
ther than to the potential to form ion pairs. We can conclude that the form
ation of ion pairs may not be very efficient as a strategy to enhance trans
epithelial transport of charged hydrophilic compounds, as competition by ot
her ions may abolish the beneficial effect of counter ions. (C) 1999 Elsevi
er Science B.V. All rights reserved.