Partitioning of ionizable drugs

Liposome partitioning of ionizable drugs can be determined by titration, and has been correlated with human absorption [102-104]. A new absorption potential parameter has been suggested, as calculated from liposome distribution data and the solubility-dose ratio, which shows an excellent sigmoidal relationship with human passive intestinal absorption (Eq. 2) [102, 103]. 

K Balon, BU Riebesehl, BW Muller. Determination of liposome partitioning of ionizable drugs by titration. J Pharm Sci 88 802-806, 1999. 

Tab. 4.1 Partitioning of ionizable drugs (see pKa) into small unilamellar vesicles (SUVs) of DOPC and into octanol for uncharged and charged species, determined by the potentiometric titration technique, compared with their intestinal absorption (%) at the doses indicated. (Adapted from Tab. 2 of ref. 16)... 

Balon K, Riebesehl BU, Muller BW (1999) Drug liposome partitioning as a tool for the prediction of human passive intestinal absorption. Pharm Res 16 882-888 Balon K, Riebesehl BU, Muller BW (1999) Determination of liposome partitioning of ionizable drugs by titration. J Pharm Sci 88 802-806... 

Liposomes, which are lipid bilayer vesicles prepared from mixtures of lipids, also provide a useful tool for studying passive permeability of molecules through lipid. This system, for example, has been used to demonstrate the passive nature of the absorption mechanism of monocarboxylic acids [116]. Liposome partitioning of ionizable drugs can be determined by titration and has been correlated with human absorption [117-119]. Liposome partitioning is only partly correlated with octanol/ water distribution and might contain some additional information. 

Avdeef, A., Box, K. J., Comer, J. E., Hibbert, C., Tam, K. Y. pH-metric logP 10. Determination of liposomal membrane-water partition coefficients of ionizable drugs. Pharm. Res. 1998,... 

However, recent studies on the variation of the distribution coefficient of ionizable drugs as a function of pH (pH-lipophilicity profiles) shows that the partitioning of charged species cannot be neglected [143]. In other words, the general relationship between distribution and partition coefficients [Eq. (15)] cannot be simplified. 

Estimation or measurement of pKa is important to understand the state of ionization of the drug under physiological conditions and to evaluate salt-forming ability.27 Log P determines the partitioning of a drug between an aqueous phase and a lipid phase (i.e., lipid bilayer). Log P and acid pKa can be theoretically estimated with reasonable accuracy.14,28,29 High-throughput methods are also available for measurement of log P30 and pKa.31... 

The ion pairing approach involves coadministration of a hydrophilic or polar drug with a suitable lipophilic counterion, which consequently improves the partitioning of the resultant ion pair (relatively more lipophilic) into the intestinal membrane. In fact, the approach seems to increase the oral bioavailability of ionizable drugs, such as atenolol, by approximately 2-fold.However, it is important that a counterion possess high lipophilicity, sufficient aqueous solubility, physiological compatibility, and metabolic stability. Some of the successful applications of this approach have already been described in previous reviews " and therefore, will not be described any further here. 

Avdeef A, Box KJ, Comer JEA, Hibbert C and Tam KY, pH-metric log P 10. Determination of liposomal membrane-water partition coefficients of ionizable drugs, Pharm. Res., 15(2), 209-215 (1998). NB Used a Sirius PCAlOl autotitrator. Also gave log P (octanol-water) and log P (dioleylphosphatidylcholine unilamellar veacles). See also Lidocaine (no. 741). The same results were also given in Sirius Technical Application Notes, vol. 2, p. 94-95 (1995). Sirius Analytical Instruments Ltd., Forest Row, East Sussex, RH18 5DW, UK. 

Uhneanu, S. M., H. Jensen, G. Bouchard, P. A. Carrupt, and H. H. Girault, Water-oil partition prohhng of ionized drug molecules using cyclic voltammetry and a 96-well microfilter plate system, Pharmaceut Res, Vol. 20, (2003) p. 1317. 

The evaluation of the apparent ionization constants (i) can indicate in partition experiments the extent to which a charged form of the drug partitions into the octanol or liposome bilayer domains, (ii) can indicate in solubility measurements, the presence of aggregates in saturated solutions and whether the aggregates are ionized or neutral and the extent to which salts of dmgs form, and (iii) can indicate in permeability measurements, whether the aqueous boundary layer adjacent to the membrane barrier, Umits the transport of drugs across artificial phospholipid membranes [parallel artificial membrane permeation assay (PAMPA)] or across monolayers of cultured cells [Caco-2, Madin-Darby canine kidney (MDCK), etc.]. 

Hence, two drugs of similar ogP may differ greatly in logZ) at physiological pH, with profound consequences for their pharmacological activity. As a consequence, log/ values of ionizable compounds are often quoted at pH 7.4, and equations similar to those above are used in pH-metric techniques [117-124] to determine either log/ or logZ). A compilation of the principal relationships linking partition and distribution coefficients is available in Refs. 125 and 126. 

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