[Introduction] Oral bioavailability (F) is a product of absorption (Fa), intestinal availability (Fg), and hepatic availability (Fh) (F = FaFg x Fh). While Fh has been investigated extensively, recent studies have focused more on FaFg instead. In the present study, an in-house compound B* was used to investigate factors affecting FaFg in rats, since intestinal absorption/metabolism is known to influence pharmacokinetics in rats, as revealed by the low FaFg value (0.15) using the portal-systemic difference method. [Methods and Results] Metabolic stability in rat intestinal microsomes showed that compound B is stable against rat intestinal cytochrome P450 enzymes. Parallel artificial membrane permeable assay (PAMPA) experiments indicated that compound B is highly permeable with a permeability value of 14 x 10-6 cm/s. However, experiments using cells stably expressing human multidrug resistance (MDR1) showed the apparent permeability to be 0.45 x 10-6 cm/s for apical to basal flux, and 29.7 x 10-6 cm/s for basal to apical flux, indicating that compound B is a typical substrate of P-glycoprotein (P-gp). Pharmacokinetic studies using normal mice and mdr1a-deficient (KO) mice showed that the respective FaFg values of compound B were 0.25 and almost 1.0, indicating that intestinal P-gp limited the intestinal absorption of compound B. [Conclusion] Our present findings suggest that the low FaFg of compound B in rats is caused by intestinal P-gp, implying that intestinal P-gp substantially affects bioavailability by limiting intestinal absorption (Fa) in rats .
*The structure of compound B is totally different from compound A used in the study of “Substantial impact of P-glycoprotein on bioavailability in rats (1)”.