Comparative maternal and fetal pharmacokinetic parameters of the unbound and total VPA in five pregnant ewes during late gestation
| Unbound VPA | Total VPA | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| CLutb | t1/2uβ | MRTu | Vduss | CLtb | t1/2β | MRT | fp | Vdss | Vdss′4-a | |
| Maternal | ||||||||||
| E4241 | 4.1 | 5.0 | 2.9 | 0.70 | 1.3 | 4.2 | 4.4 | 0.32 | 0.34 | 0.22 |
| E5108 | 7.0 | 4.0 | 3.1 | 1.29 | 2.3 | 5.3 | 4.6 | 0.33 | 0.63 | 0.42 |
| E105x | 1.4 | 7.4 | 5.8 | 0.47 | 0.6 | 7.3 | 8.4 | 0.46 | 0.32 | 0.22 |
| E4133 | 8.3 | 3.5 | 1.5 | 0.73 | 1.7 | 4.5 | 2.4 | 0.21 | 0.24 | 0.15 |
| E1226 | 6.0 | 7.5 | 2.3 | 0.83 | 1.5 | 6.7 | 3.6 | 0.24 | 0.32 | 0.20 |
| Mean ± S.D. | 5.4 ± 2.7 | 5.5 ± 1.9 | 3.1 ± 1.64-b | 0.80 ± 0.30 | 1.5 ± 0.6 | 5.6 ± 1.4 | 4.7 ± 2.3 | 0.31 ± 0.10 | 0.37 ± 0.15 | 0.24 ± 0.10 |
| Fetal | ||||||||||
| E4241 | 62.4 | 3.8 | 1.8 | 6.65 | 20.4 | 4.8 | 3.2 | 0.33 | 3.89 | 2.18 |
| E5108 | 86.1 | 2.4 | 1.0 | 4.92 | 17.5 | 4.3 | 2.0 | 0.20 | 2.07 | 1.00 |
| E105x | 30.3 | 5.0 | 4.2 | 7.72 | 10.1 | 7.4 | 6.3 | 0.33 | 3.84 | 2.57 |
| E4133 | 52.1 | 1.9 | 1.7 | 5.31 | 16.5 | 2.1 | 1.9 | 0.32 | 1.87 | 1.68 |
| E1226 | 79.8 | 2.3 | 1.5 | 6.97 | 16.9 | 4.5 | 1.8 | 0.21 | 1.86 | 1.48 |
| Mean ± S.D. | 62.1 ± 22.44-c | 3.1 ± 1.34-b 4-d | 2.0 ± 1.34-a | 6.31 ± 1.174-e | 16.3 ± 3.84-c | 4.6 ± 1.9 | 3.0 ± 1.9 | 0.28 ± 0.07 | 2.70 ± 1.064-e | 1.78 ± 0.614-e |
↵4-a VDss′: corrected steady-state volume of distribution of the total drug in liters per kilogram; fp: area weighted unbound fraction of the drug. Superscript ‘u’ in the above symbols refers to the same pharmacokinetic parameters for the unbound drug.
↵4-b Significantly shorter than fetalt1/2β (P < .05).
↵4-c Significantly higher than the corresponding maternal values (P < .005).
↵4-d Significantly shorter than maternalt1/2uβ (P < .05).
↵4-e Significantly shorter than the corresponding total VPA MRT (P < .05).
4-f Significantly larger than the corresponding maternal volume parameter (P < .0005).