Mechanistic study of absorption and first-pass metabolism of GL-V9, a derivative of wogonin.

GL-V9, a derivative of wogonin, has potent anti-cancer activity. The absorption and metabolism of this compound have not been investigated systematically. This study aims to illustrate the pharmacokinetic characters of GL-V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL-V9, an in situ single-pass perfusion model and a Caco-2 cell monolayer model were used. Meanwhile, a microsomal incubation system was used to evaluate the enzyme kinetic parameters. In vivo, the obtained gastrointestinal availability (F-a x F-g) was 21.28 +/- 5.38%. The unmetabolized fraction in the gut wall (F-gut wall) was 98.59 +/- 9.74%, while the hepatic bioavailability (F-h) was 29.11 +/- 5.22%. These results indicated that poor absorption and extensive metabolism may contribute greatly to the low bioavailability of GL-V9. The effective permeability (P-eff) in the duodenum and jejunum was 1.34 +/- 0.50 x 10(-4) and 0.90 +/- 0.27 x 10(-4) cm/s, respectively. The high permeability of GL-V9 indicated that other unknown factors (such as metabolism) may account for its systemic exposure problem. Studies in rat liver microsomal (RLMs) confirmed this hypothesis, and the Cl-int,Cl- CYP450s and UGT of GL-V9 was 0.20 ml/min/mg protein. In conclusion, these results suggest that GL-V9 possesses higher permeability than wogonin and the metabolism of GL-V9 is related to its disposition in rat intestine and liver.