Permeability jejunal

Winiwarter, S., Bonham, N. M., Ax, F., Hallberg, A., Lennemas, H., Karlen, A. Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach. J. Med. Chem. 1998, 41, 4939-4949. 

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] ... 

Bioavailability depends not only on having the drug in solution, but also on the drug s permeability. A jejunal permeability of at least 2-4 x 10 4cm/s, measured in human subjects by intubation, is considered high [97]. For many drugs and other substances, this permeability corresponds to a fraction absorbed of 90% or better. Amidon et al. [97] thus proposed a Biopharmaceutics Classification System (BCS) for drugs based on the above definitions of these two parameters. Table 3 defines the BCS and includes some drugs representative of each class. 

The strategy for the development of the oral absorption model at pION is illustrated in Fig. 7.58. The human jejunal permeabilities reported by Winiwarter et al. [56] were selected as the in vivo target to simulate by the in vitro model. In particular, three acids, three bases and two nonionized molecules studied by the University of Uppsala group were selected as probes, as shown in Fig. 7.58. They are listed in the descending order of permeabilities in Fig. 7.58. Most peculiar in the ordering is that naproxen, ketoprofen, and piroxicam are at the top of the list, yet these three acids are ionized under in vivo pH conditions and have lipophilicity (log Kj) values near or below zero. The most lipophilic molecules tested, verapamil and carbamazepine... 

Figure 7.59 Human jejunal permeabilities compared to Caco-2 permeabilities from several groups.

How Well Do Caco-2 Permeability Measurements Predict Human Jejunal Permeabilities ... 

Since the widely accepted in vitro permeability model in the pharmaceutical industry is based on the use of cultured cells, such as Caco-2 or MDCK, it was appropriate to analyze the regression correlation coefficients based on the comparisons of Caco-2 log Pe and the log Pe values based on the human jejunal measurements [56]. 

Figure 7.59 shows a plot of logP JP (human jejunal permeabilities) vs. log pCaco-2 takgjj from the literature, based on the work of more than 11 laboratories. The r2 for the correlation is 0.62. It is clear from the plot that some laboratories better predicted the HJP than other laboratories. Figure 7.60 shows the plot of the results published by Artursson s group [506,512,603], where r2 was calculated as 0.95, the most impressive value of all the comparisons. It is noteworthy that naproxen, ketoprofen, and piroxicam were not available for the comparison in the Fig. 7.60 plot. 

Table 7.23 shows the results for 47 specific PAMPA models tested at pION, according the the scheme in Fig. 7.58. The two columns on the right are the r2 values in the comparisons. The neutral-lipid models (1.0, 1A.0, 2.0, 3.0, and 4.0) at pH 7.4 do not explain the permeability trend indicated in the human jejunal permeabilities [56]. Octanol was least effective, with r2 0.01. This should not be too surprising, since we did note that the appearance of naproxen, ketoprofen, and piroxicam at the top of the HJP ordering was unexpected. Our expectations were based on the octanol-water lipophilicity scale, which clearly does not correlate with the HJP trend. Adding a sink condition to the 2% DOPC model (model 1.1) improves correlation (r1 increases from 0.33 to 0.53). The addition of cholesterol to the 2% DOPC/dodecane system made the model unstable to the surfactant-created sink condition. 

TABLE 7.23 Correlation (r) between Human Jejunal and PAMPA Permeabilities... 

Figure 7.61 Correlation between human jejunal permeabilities and soy lecithin models (in dodecane) at pH 7.4.

Figure 7.62 Correlation between human jejunal permeabilities [vs. PAMPA (double-sink)] and soy lecithin models under gradient pH conditions.

Figure 7.63 Human jejunal permeabilities compared to pION s double-sink sum-Pe PAM PA GIT model.

The pION double-sink GIT model, with donor pH 5, predicts the human jejunal permeabilities as well as the best reported Caco-2 model (Artursson s), and a lot better than the rest of the reported Caco-2 models, as shown in Fig. 7.63. 

Figure 7.67 Human intestinal absorption compared to (a) pION s double-sink sum-P, PAMPA GIT model and (b) human jejunal permeabilities [56],...

The lengthy permeability chapter (Chapter 7) recounts the study of many different artificial membrane formulations, comparing transport results of each to human jejunal permeabilities. A very promising in vitro screening system was described the double-sink sum-Pe PAMPA GIT model. It is most applicable to molecules that are classified as soluble in the BCS scheme. 

H Lennernas, S Nylander, AL Ungell. Jejunal permeability A comparison between the Ussing chamber technique and the single-pass perfusion in humans. Pharm Res 14 667-671, 1997. 

H Lennernas. Human jejunal effective permeability and its correlation with preclini-cal drug absorption models. J Pharm Pharmacol 49 627-638, 1997. 

Predictions of in vivo Human Jejunal Permeabilities using the Improved 20% Soy Lecithin with Surfactant in vitro PAMPA Technique... 

The studies of various compositions revealed that the 20% soy lecithin-dodecane membrane with 35 mM in the acceptor wells has substantially improved predictive value compared with the 2% DOPC model. Fine-tuning of the model components may be guided by the in vitro-in vivo (IV-IV) correlations, comparing the improved PAMPA model permeabilities to the human jejunal permeabilities measured by Winiwarter et al. [36] (Table 3.6). Table 3.7 lists the results of comparisons of various models. The best correlations were realized with the 20% soy lecithin-dodecane system, employing 35 mM SLS in the acceptor compartment, but a better... 

Tab. 3.7. in vitro-in vivo correlations, PAMPA versus human jejunal permeabilities. 

Fig. 3.7. Correlation between human jejunal and PAMPA permeabilities (see Tab. 3.7 and text).

Fig. 7.12. Effective permeability (Peff) of kinetic studies. The higher jejunal Peff of...

---