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10 100 Caco-2 cell permeability (nm/sec)

10 100 Caco-2 cell permeability (nm/sec)

1000

Figure 5.2. Correlation of (a) PAMPA permeability and (b) Caco-2 cell permeability with the extent of absorption in humans for marketed drugs. These drugs are known to be primarily absorbed via passive diffusive pathway. Each point is the mean of three or more repeats. The dotted line represents a cut-off of 100 nm/s

5. Evaluation of Permeability and P-glycoprotein Interactions 119 Table 5.3. PAMPA and Caco-2 cell permeability values of marketed drugs

Drug PAMPA permeability Caco-2 Cell Percentage of fraction

5. Evaluation of Permeability and P-glycoprotein Interactions 119 Table 5.3. PAMPA and Caco-2 cell permeability values of marketed drugs

Drug PAMPA permeability Caco-2 Cell Percentage of fraction

(nm/s)

permeability (nm/s)

absorbed in humans

Acebutalol

16 ± 11

40 ± 4

55

Alprenolol

299 ± 68

111 ± 30

93

Amiloride

5 ± 3

49 ± 8

50

Cimetidine

22 ± 3

29 ± 12

79

Desipramine

700 ± 170

300 ± 21

95

Dexamethasone

287 ± 11

134 ± 13

95

Etoposide

35 ± 4

18 ± 10

50

Fenaterol

3 ± 1

na

60

Furosemide

9 ± 1

20 ± 4

66

Hydralazine

105 ± 4

141 ± 16

90

Ketoconazole

542 ± 37

108 ± 18

76

Ketoprofen

22 ± 6

250 ± 26

90

Metformin

5 ± 2

12 ± 3

52

Metoprolol

266 ± 16

120 ± 10

95

Naproxen

33 ± 3

300 ± 41

100

Norfloxacin

5 ± 1

19 ± 3

35

Phenytoin

204 ± 9

310 ± 15

90

Propranolol

411 ± 110

175 ± 26

90

Sulfasalazine

2 ± 1

4 ± 1

12

Sulpiride

3 ± 1

5 ± 2

35

Terbutaline

3 ± 1

15 ± 6

50

Verapamil

399 ± 112

98 ± 19

95

na not available

were "high" permeability (quadrant 2). The compounds that fell in quadrants 1 and 4 were the disconnects between the two permeability models. The disagreement observed for ~20% of the compounds highlights the fundamental difference between the two models. PAMPA is an absorption model that captures uncontam-inated transcellular diffusion across the lipid bilayers. It is completely devoid of any influx/efflux transporters or paracellular pores. On the other hand, cell tight junctions and various drug transporters (influx:PepT1 and efflux: P-gp, MRP2, BCRP, etc.) are expressed in the Caco-2 cell monolayer. The compounds shown in quadrant 4 (high PAMPA and low Caco-2 cell permeability) are likely to be substrates of efflux transporters that would limit their permeability in Caco-2 cell model. Because the PAMPA is a simple lipid bilayers, the permeability of compounds in quadrant 4 remain high. A handful of compounds from the quadrant 4 were evaluated for their P-gp substrate potential by performing bidirectional transport study in Caco-2 cells. As expected, they were all shown to be substrates with efflux ratio (ratio of B to A/A to B) higher than 3. The quadrant 1 represents compounds that have high Caco-2 cell permeability and low PAMPA permeability. Compounds in quadrant 1 are likely to permeate Caco-2 cell monolayer via para-cellular pores and/or influx transporters. In general, a good agreement between the two permeability models for passively absorbed compounds is expected. If there is disagreement between these two models, it may provide a hint that specific influx

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