TABLE 1.
Physicochemical properties, metabolic stability, permeability, and net P-gp flux ratios of cationic diamidinesa
| Compound | pKa | LogP | LogD7.4 | Concn (μM) | Microsomal t1/2 (min)b | Value in indicated cell culture |
Net flux ratio | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MDR1-MDCK |
WT MDCK |
|||||||||||
| Papp,A-B (10−6 cm/s) | Mass balance (%) | Efflux ratio (Papp,B-A/Papp,A-B) | Papp,A-B (10−6 cm/s) | Mass balance (%) | Efflux ratio (Papp,B-A/Papp,A-B) | |||||||
| Pentamidine | 11.60 ± 0.01 | 1.7 ± 0.1 | <−2.0 | 1 | >180 | 1.6 ± 1.1d | 99 | 1.2 | 0.54 ± 0.40 | 92 | 2.2 | 0.55 |
| 10 | >180 | 1.6 ± 0.60 | 98 | 3.1 | 0.99 ± 0.47 | 94 | 4.9 | 0.63 | ||||
| DB75 | 11.80 ± 0.01 | 2.7 ± 0.1 | <−2.0 | 1 | >180 | 4.1 ± 1.1d | 105 | 0.5 | 4.8 ± 0.96c | 102 | 0.6 | 0.83 |
| 10.40 ± 0.03 | 10 | >180 | 2.5 ± 0.97 | 96 | 0.9 | 1.4 ± 0.52c | 92 | 2.4 | 0.38 | |||
| DB820 | 11.03 ± 0.29 | 1.65 ± 0.13 | −4.90 | 1 | >180 | 2.5 ± 0.42 | 98 | 0.8 | 5.4 ± 1.7 | 102 | 0.6 | 1.3 |
| 10.32 ± 0.15 | 10 | >180 | 2.8 ± 1.4 | 96 | 0.7 | 3.1 ± 1.3 | 98 | 0.9 | 0.78 | |||
| DB829 | 10.35 ± 0.18 | 1.21 ± 0.20 | −4.33 | 1 | >180 | 2.8 ± 0.30c | 102 | 0.8 | 1.9 ± 0.68 | 103 | 0.95 | 0.84 |
| 9.98 ± 0.16 | 10 | >180 | 1.8 ± 0.31c | 102 | 0.8 | 2.5 ± 0.99 | 105 | 1.3 | 0.62 | |||
| Digoxin | 10 | ND | 0.34 ± 0.08 | 90 | 25 | 0.78 ± 0.2 | 91 | 6.8 | 3.7 | |||
| Midazolam | 10 | ND | 40 ± 6.6 | 108 | 0.99 | 50 ± 2.7 | 103 | 1.02 | 0.97 | |||
a
Values are means ± standard deviations unless otherwise indicated. The Papp,A-B values are from triplicate determinations at each concentration.
b
Microsomal half-lives of diamidines were determined using NADPH-supplemented mouse liver microsomes. ND, not determined.
c
The difference between the results at 1 and 10 μM was statistically significant (P < 0.05).
d
The difference between the results for pentamidine and DB75 was statistically significant (P < 0.05).