## Info

Figure 7.20 Three-compartment equilibrium distribution model (after Kubinyi [23]).

Kubinyi [23] showed that the bilinear equation (7.43) can be approximated by a general form log C = a log Kp + c — b log (rKp + 1) (7 .44)

where a, b, c, r are empirical coefficients, determined by regression analysis, and C is the concentration in the intermediate phase. Equation (7.44) was used to calculate the curve in Fig. 7.19d.

Our present topic is the relationship between permeability and lipophilicity (kinetics), whereas we just considered a concentration and lipophilicity model (thermodynamics). Kubinyi demonstrated, using numerous examples taken from the literature, that the kinetics model, where the thermodynamic partition coefficient is treated as a ratio of two reaction rates (forward and reverse), is equivalent to the equilibrium model [23]. The liposome curve shape in Fig. 7.20 (dashed-dotted line) can also be the shape of a permeability-lipophilicity relation, as in Fig. 7.19d.

This relationship was further clarified by van de Waterbeemd in the ''two-step distribution" model [588-590]. Later, the model was expanded by van de Water-beemd and colleagues to include the effects of ionization of molecules, with the use of log Kd, in place of log Kp, as well as the effects of aqueous pores [49,54].

7.7 PAMPA: 50+ MODEL LIPID SYSTEMS DEMONSTRATED WITH 32 STRUCTURALLY UNRELATED DRUG MOLECULES

In the rest of the chapter, we describe over 50 specific PAMPA lipid models developed at pION, identified in Table 7.3. The lipid models are assigned a two

10 |L liposome

50 |L octanol

1 mL

y X. water

/ Collander equation from Fig. 5.6 / lo9 Kp,liposome = 0 41 lo9 Kp,oct + 2 04

TABLE 7.3 PAMPA Lipid Models

Model Number

Neutral |
2% DOPCa |

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