Pharmacokinetics of a novel retinoid AGN 190168 and its metabolite AGN 190299 after intravenous administration of AGN 190168 to rats

AbstractThe pharmacokinetics of AGN 190168, a novel synthetic retinoid, and its major metabolite, AGN 190299, in rat blood after intravenous administration was investigated. Approximately 4.4 mg kg−1 (high dose) or 0.49 mg kg−1 (low dose) of AGN 190168 was administered to rats via the femoral vein. Blood was collected from the femoral artery at various time points during an 8 h period. Blood concentrations of AGN 190168 and AGN 190299 were determined by a specific and sensitive high‐pressure liquid chromatographic (HPLC) method.AGN 190168 was rapidly metabolized in rats. The only detectable drug‐related species in the blood was AGN 190299. Therefore, only pharmacokinetics of AGN 190299 were calculated. Elimination of AGN 190299 appeared to be non‐linear after administration of the high dose, and linear after administration of the low dose. The maximum elimination rate (Vmax) and the concentration at half of the Vmax (km), as estimated by a Michaelis—Menten one‐compartment model, were 7.58 ± 2.42 μg min−1 (mean ± SD) and 6.10 ± 1.58 μg mL−1, respectively. The value of the area under the blood concentration time curve (AUC) was 9.54 ± 1.68 μg h mL−1 after administration of the high dose and 0.594 ± 0.095 μg h mL−1 after administration of the low dose. The clearance value was 7.79 ± 1.20 mL min−1 kg−1 after the high dose, statistically significantly different from that after the low dose (p < 0.05), 14.0 ± 2.2 mL min−1 kg−1. The terminal half‐life (t1/2) was 1.25 ± 0.74 h for the high‐dose group and 0.95 ± 0.16 h for the low‐dose group.Study results demonstrate rapid systemic metabolism of AGN 190168 to AGN 190299, non‐linear pharmacokinetics of AGN 190299 after the 4.4 mg kg−1 dose, and the lack of difference in disposition profiles between sexes after intravenous administration of AGN 190168 to rats.