Permeability and Absorption in Humans

Calculated molecular descriptors including H-bond parameters were used for QSAR studies on different types of permeabiUty. For example, the new H-bond descriptor characterizing the total H-bond ability of a compound, was successfully appUed to model Caco-2 cell permeability of 17 drugs [30]. A similar study on human jejunal in vivo permeabiUty of 22 structurally diverse compounds is described in Ref. [62]. An exceUent one-parameter correlation of human red ceU basal permeabiUty (BP) was obtained using the H-bond donor strength [63]  

A quantitative description of human skin permeabiUty (kp) based on H-bond donor and acceptor factors was obtained with 22 alcohols and steroids [63]  

QSAR studies of the pH-dependent partitioning of acidic and basic drugs into liposomes [64] yielded following equations  

For 31 passively transported dmgs, excellent sigmoidal relationships were found between human intestinal absorption and their H-bond acceptor and donor factors [65]  

A volume-related term (expressed by polarizability) and electrostatics (expressed by partial atomic charge) made minor contributions to intestinal absorption in humans. Lipophilicity, expressed by logP or logD values, shows no correlation with the human absorphon data. Recently, similar results were obtained for 154 passively transported drugs on the basis of surface thermodynamics descriptors [39]  

---

With the difficulties associated with accurate estimation of permeability based only on physicochemical properties, a variety of methods of measuring permeability have been developed and used, among which are (l)cul-tured monolayer cell systems, such as Caco-2 or MDCK ( 2 diffusion cell systems that use small sections of intestinal mucosa between two chambers (3) in situ intestinal perfusion experiments performed in anesthetized animals such as rats and (4)intestinal perfusion studies performed in humans (40,54-62). All of these methods offer opportunities to study transport of drug across biological membranes under well-controlledconditions. Caco-2 mono-layer systems in particular have become increasingly commonly used in recent years and human intestinal perfusion methods are also becoming more commonly available. Correlations between Caco-2 permeability and absorption in humans have been developed in several laboratories (63-72). As shown in Fig. 

---