In Vitro Double-Sink PAMPA Models for GIT and BBB Targets in Visual Studio .NET

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TABLE 722
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In Vitro Double-Sink PAMPA Models for GIT and BBB Targets
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In Vivo GIT In Vivo BBB 0 74/74 No No 27 In Vitro Double-Sink GIT Model (20% Soy Lecithin) 2300!30 (corr) 50/74, 62/74, 74/74 Yes Yes 16 In Vitro Double-Sink BBB Model (20% Soy Lecithin) 2300!0 (corr) 74/74 No No 16
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Unstirred water layer (mm) 30 100 pH donor/receiver 5 8 /74 Receiver sink Yes Mixed micelles in lumena Yes Negative-charge lipids (% wt/wt) 13 Cholesterol triglycerides cholesterol ester (% wt/wt) 37
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Proposed simulated intestinal uid containing fasted-state mixed micelle, 3 mM sodium taurocholate 075 mM lecithin, or fed-state mixed micelle, 15 mM sodium taurocholate 375 mM lecithin [61]
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THE OPTIMIZED PAMPA MODEL FOR THE GUT
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the brain, lipophilic molecules accumulate in the endothelial cells Consequently, the in vitro GIT model calls for a sink condition; the BBB model does not 4 Highly insoluble molecules are in part transported in the GIT by partitioning into the mixed micelles injected into the lumen from the biliary duct in the duodenum (Fig 23) Mixed micelles consist of a 4 : 1 mixture of bile salts and phospholipids (Fig 713) In contrast, at the point of absorption in the BBB, highly insoluble molecules are transported by serum proteins This distinction is expected to be important in in vitro assay modeling The use of simulated intestinal uids is appealing 5 The GIT has about 13% wt/wt negatively charged lipid-to-zwitterionic phospholipid ratio It is about twice as large in the BBB Factoring this into the in vitro model is expected to be important 6 The white fat content of the GIT is higher than that of the BBB The use of triglycerides and cholesterol in in vitro modeling seems important The strategy for the development of the oral absorption model at pION is illustrated in Fig 758 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 758 They are listed in the descending order of permeabilities in Fig 758 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 Kd values near or below zero The most lipophilic molecules tested, verapamil and carbamazepine
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PROBES
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in vitro SCREENS 50+ PAMPA lipid models
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in vivo TARGET
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naproxen ketoprofen piroxicam verapamil carbamazepine propranolol metoprolol hydrochlorothiazide
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HUMAN JEJUNAL PERMEABILITIES
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Strategy for oral absorption model (from Winiwarter et al [56])
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PERMEABILITY
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log Pe
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= -083 + 0580 log Pe
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Caco-2
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r = 062, s = 049, n = 60
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log Pe HJP
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Ref 553 Refs 56,74 Ref 563 Refs 97,611 Ref 602 Refs 506,512,603 Ref 82 Ref 604 Refs 605,606 Refs 608,609 Ref 610
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Best fit
log Pe Caco-2
Figure 759 Human jejunal permeabilities compared to Caco-2 permeabilities from several groups
(log Kd $ 2:5; cf Table 74), are in second rank ordering We took it as a challenge to explain these anomalies in our optimized in vitro GIT model As Fig 758 indicates, our task was to explain the ordering of the eight probe molecules in the human in vivo target, but subjecting the eight probe molecules to each of the 50 PAMPA lipid models For each PAMPA model, the regression correlation coef cient, r2, was used to assess the appropriateness of the model 782 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 coef cients based on the comparisons of Caco-2 log Pe and the log Pe values based on the human jejunal measurements [56] Figure 759 shows a plot of log PHJP (human jejunal permeabilities) vs log e Caco-2 Pe taken from the literature, based on the work of more than 11 laboratories The r 2 for the correlation is 062 It is clear from the plot that some laboratories better predicted the HJP than other laboratories Figure 760 shows the plot of the results published by Artursson s group [506,512,603], where r 2 was calculated as 095, 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 760 plot