Table 3.
Pharmacokinetic parameters of itraconazole, 7-hydroxyitraconazole and metformin after single p.o. administration of itraconazole 20 mg·kg−1, metformin 100 mg·kg−1 or both drugs together to rats
| Itraconazole | Metformin | ||||
|---|---|---|---|---|---|
| Parameter | Without metformin (n = 6) | With metformin (n = 9) | Parameter | Without itraconazole (n = 7) | With itraconazole (n = 9) |
| Itraconazole | Metformin | ||||
| AUC (µg·min−1·mL−1) | 1370 ± 377 | 2320 ± 525* | AUC (µg·min−1·mL−1) | 2930 ± 660 | 5340 ± 1260** |
| Terminal half-life (min) | 969 ± 268 | 1140 ± 533 | Terminal half-life (min) | 253 ± 38.8 | 490 ± 177* |
| CLR (mL·min−1·kg−1) | 0.0307 ± 0.0308 | 0.00643 ± 0.00795 | CLR (mL·min−1·kg−1) | 30.9 ± 8.27 | 16.9 ± 3.44** |
| Cmax (µg·mL−1) | 1.20 ± 0.318 | 1.29 ± 0.403 | Cmax (µg·mL−1) | 13.9 ± 2.11 | 8.15 ± 1.74** |
| Tmax (min) | 480 (120 to 720) | 360 (120 to 720)*** | Tmax (min) | 60 (15 to 120) | 120 (15 to 360)** |
| Ae0–48h (% of itraconazole dose) | 0.182 ± 0.199 | 0.0670 ± 0.0742 | Ae0–48h (% of metformin dose) | 86.2 ± 11.2 | 87.2 ± 12.1 |
| GI48h (% of itraconazole dose) | 0.309 ± 0.153 | 0.342 ± 0.195 | GI48h (% of metformin dose) | 6.05 ± 3.70 | 4.76 ± 2.21 |
| F (%) | 57.3 | 68.4 | F (%) | 42.8 | 56.2 |
| 7-Hydroxyitraconazole | |||||
| AUC (µg·min−1·mL−1) | 2520 ± 316 | 2170 ± 274*** | |||
| Terminal half-life (min) | 1180 ± 426 | 1190 ± 381 | |||
| CLR (mL·min−1·kg−1) | 0.00564 ± 0.00453 | 0.00379 ± 0.00174 | |||
| Cmax (µg·mL−1) | 1.30 ± 0.453 | 0.844 ± 0.109*** | |||
| Tmax (min) | 720 (720 to 1800) | 1440 (30 to 360)*** | |||
| Ae0–48h (% of itraconazole dose) | 0.187 ± 0.161 | 0.0919 ± 0.0394 | |||
| GI48h (% of itraconazole dose) | 0.315 ± 0.108 | 0.346 ± 0.152 | |||
| AUC7-hydroxyitraconazole/AUCitraconazole | 190 ± 34.4 | 98.5 ± 27.7** | |||
Data are expressed as means ± SD.
Significantly different from without metformin or without itraconazole
*
P < 0.01
**
P < 0.001
***
P < 0.05.
Ae0–48h, percentage of the dose excreted in the 48 h urine; AUC, total area under the plasma concentration–time curve from time zero to infinity; CLR, time-averaged renal clearance; Cmax, peak plasma concentration; F, extent of absolute oral bioavailability; GI48h, percentage of the dose recovered from the entire gastrointestinal tract (including its contents and feces) at 48 h; Tmax, time to reach Cmax.