Relevant pharmacokinetic parameters for metabolites of IF enantiomers in control and PB-treated rats given IF pseudoracemate (40 mg/kg)
| Pharmacokinetic Parameters2-a | HOIF | N2D | N3D2-b | IPM | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Control2-c | R/S2-d | Treated | R/S | Control | R/S | Treated | R/S | Control | R/S | Treated | R/S | Control | R/S | Treated | R/S | ||
| λ (×10−3min−1) | R | 18.1 ± 3.1 | 68.9 ± 21.0 | 4.30 ± 0.672-e | 10.3 ± 3.32-e | 3.79 ± 1.042-e | 17.8 ± 11.7 | 9.58 ± 2.48 | 34.2 ± 7.8 | ||||||||
| S | 16.6 ± 1.4 | 1.09 | 69.9 ± 38.4 | 1.08 | 3.39 ± 0.782-e | 1.29 | 7.65 ± 2.192-e | 1.34 | 4.42 ± 1.282-e | 0.864 | 10.9 ± 2.5 | 1.74 | 9.34 ± 2.87 | 1.04 | 35.2 ± 7.4 | 0.971 | |
| t 1/2λ (min) | R | 39.2 ± 5.9 | 10.9 ± 3.32 | 164 ± 242-e | 73.0 ± 22.12-e | 196 ± 58 | 52.7 ± 25.5 | 75.7 ± 15.5 | 21.1 ± 4.6 | ||||||||
| S | 41.9 ± 3.4 | 0.935 | 11.8 ± 4.2 | 0.987 | 211 ± 422-e | 0.791 | 96.2 ± 24.12-e | 0.754 | 167 ± 44 | 1.18 | 65.8 ± 11.8 | 0.846 | 78.3 ± 16.1 | 0.974 | 20.4 ± 4.1 | 1.03 | |
| AUC (μM · min) | R | 376 ± 1162-e | 224 ± 62 | 799 ± 2072-e | 229 ± 1072-e | 1380 ± 519 | 192 ± 912-e | 1304 ± 2882-e | 729 ± 101 | ||||||||
| S | 221 ± 602-e | 1.70 | 237 ± 64 | 0.945 | 2794 ± 6072-e | 0.287 | 1205 ± 4472-e | 0.186 | 966 ± 192 | 1.41 | 1175 ± 3152-e | 0.159 | 867 ± 1772-e | 1.50 | 717 ± 107 | 1.02 | |
| AUCm/AUCp (%) | R | 8.77 ± 3.972-e | 16.6 ± 6.4 | 17.4 ± 4.22-e | 15.6 ± 3.42-e | 24.7 ± 13.4 | 13.8 ± 3.92-e | 31.8 ± 16.42-e | 51.1 ± 23.7 | ||||||||
| S | 4.02 ± 1.682-e | 2.18 | 18.7 ± 6.5 | 0.920 | 48.5 ± 14.32-e | 0.365 | 90.5 ± 18.92-e | 0.172 | 22.2 ± 8.6 | 1.09 | 83.7 ± 17.72-e | 0.173 | 16.5 ± 8.32-e | 1.92 | 53.0 ± 19.0 | 0.946 | |
| C max (μM) | R | 5.90 ± 1.962-e | 11.2 ± 1.9 | 2.98 ± 0.712-e | 2.06 ± 0.422-e | 4.82 ± 1.85 | 2.64 ± 0.712-e | 11.6 ± 2.72-e | 18.5 ± 2.5 | ||||||||
| S | 3.38 ± 1.132-e | 1.77 | 11.5 ± 1.8 | 0.977 | 7.75 ± 1.762-e | 0.384 | 8.33 ± 1.572-e | 0.248 | 3.74 ± 0.84 | 1.27 | 12.0 ± 2.42-e | 0.224 | 7.35 ± 1.672-e | 1.59 | 18.6 ± 3.4 | 1.01 | |
| U (% of dose in 36-hr urine) | R | 2.12 ± 0.772-e | 1.30 ± 0.27 | 4.48 ± 0.652-e | 1.50 ± 0.682-e | 5.76 ± 1.68 | 1.41 ± 0.632-e | 29.4 ± 5.82-e | 27.9 ± 3.8 | ||||||||
| S | 1.15 ± 0.362-e | 1.85 | 1.30 ± 0.25 | 1.00 | 14.0 ± 2.82-e | 0.328 | 6.89 ± 1.702-e | 0.212 | 4.10 ± 1.06 | 1.42 | 7.53 ± 2.052-e | 0.185 | 19.1 ± 2.62-e | 1.53 | 28.5 ± 3.8 | 0.984 | |
Values are mean ± SD. All N = 6.
↵2-a λ, terminal decay rate constant; AUCm, metabolite AUC; AUCp, parent drug AUC; Cmax, peak concentration; U, urinary excretion.
↵2-b (R)- and (S)-N3D are generated from (S)- and (R)-IF, respectively.
↵2-c The differences in all parameters between R- andS-isomers for the control and PB-treated groups were not statistically significant, except for those indicated,p = 0.01.
↵2-d R and S refer to metabolites with the configuration of R or S, and (R)- and (S)-IPM refer to compounds generated from (R)- and (S)-IF, respectively.
↵2-e Difference between R and S isomers atp < 0.01.