05, n = 4) c Apparent volume of distribution was significantly effected by the route of administration (p = 0.002) Careful consideration of the apparent volume of distribution and clearance suggests that volume of distribution

is affected to a greater extent by oral administration than for clearance. The apparent volume of distribution for FA was significantly higher (p = 0.002) following IV administration (251 ± 28 ml) versus find more oral administration (182 ± 27 ml). Clearance values for the two routes of administration were not significantly different (p = 0.8). Very little of the FA administered by IV was excreted unchanged in the urine. Following IV administration of 10 or 25 mg/kg, 1.7 and 2.0 % FA was excreted in urine (24 h). 3.3 IV Dose Effects FA was well tolerated in rats at IV doses of 10, 25, and 75 mg/kg with no adverse effects observed. The pharmacokinetics were not well behaved and the results, which are summarized in Tables 2 and 3, suggest non-linear pharmacokinetic behavior for FA over the dose range studied. While there was larger than expected variation in the clearance at 10 mg/kg (47 ± 34 mL/h), there was no significant difference in the clearance at any of the doses studied. The clearance at 25 and 75 mg/kg was 81 ± 14 and 40 ± 5 mL/h, respectively. Though statistical differences in clearance at these doses were not observed, the data are strongly suggestive

click here of non-linear pharmacokinetics. The effects of dose on maximum concentration (C max) and time to C max (T max) are clearly important since

these parameters are directly related to the rate and extent of absorption. Since these dose effects were not determined here, these studies should be undertaken in the future. Table 3 Effects of dose on IV pharmacokinetic parameters of fusaric acid in www.selleckchem.com/products/ABT-888.html Sprague Dawley rats PK parameter Dose 10 mg/kg 25 mg/kg 75 mg/kg t ½ (min) 40.3 ± 19.2 32.7 ± 6.6 41.4 ± 2.8 AUC∞ (mol-min/L) 26723 ± 17931 26408 ± 4480 157283 ± 19338 Vd (ml) 135.7 ± 30.8 251 ± 28 161.5 ± 25.0 CL Clomifene (min/ml-kg) 3.07 ± 2.4 5.4 ± 0.9 2.70 ± 0.3 AUC ∞ area under the serum concentration–time curve from zero to infinity, CL clearance, PK pharmacokinetic, T ½ half-life, Vd volume of distribution 4 Discussion Few descriptions of the pharmacokinetics of FA can be found in the literature. Matsuzaki et al. reported the disposition of FA following an oral dose of 20 mg/kg in the rat [15]. In this study, the acyl carbon was labeled with the radioisotope and total radioactivity in various tissues was determined. Peak radioactivity was achieved in 30 minutes with a calculated FA concentration of 42 ± 7.4 µg/mL. These results are in good agreement with the results reported here and shown in Table 2. A concentration of 290 µM is equivalent to 52 ± 11 µg/mL FA. A simple unpaired t-test indicates that there is no significant different in the C max reported herein and that reported by Matsuzaki et al. [15] (p = 0.24, alpha 0.05, 95 % clearance).