Monoketocholate can decrease transcellular permeation of methotrexate across Caco-2 cell monolayers and reduce its intestinal absorption in rat

Objectives Bile salts have been shown to decrease the absorption of methotrexate in the rat intestine by all Unknown mechanism. We aimed to examine this effect. Methods We assessed apical-to-basolateral (AP-BL) permeation of methotrexate (5 pm) across Caco-2 cell monolayers pretreated with various concentrations (0, 0.25 0.5. 1, 3 and 5 mM) of sodium cholate or its semisynthetic analogue, sodium 12-monoketocholate. We also determined the effect of orally administered 12-monoketocholate oil the intestinal absorption of methotrexate ill rats to evaluate a possible in-vitro-in-vivo correlation. Key findings It was found that sodium cholate and sodium 12-monoketocholate decreased the AP-BL permeation of methotrexate at low concentrations (maximal inhibition at 0215 and 1 mM, respectively) and increased it at higher concentrations. Determination of [C-14] mannitol permeation and electrical resistance of monolayers during experiments showed that membrane integrity was not compromised at low concentrations of bile salts but was disrupted at higher concentrations. Subsequently, we examined the effect Of the simultaneously oral administration Of sodium 12-monoketocholate (4, 20, 40 and 80 mg/kg) oil the intestinal absorption of methotrexate in rats after all oral dose (5 mg/kg). The pharmacokinetic study showed that 12-monoketocholate at 4 and 20 mg/kg did not change the methotrexate area Under the serum Concentration-time curve whereas sodium 12-monoketocholate at 40 and 80 mg/kg significantly reduced it. Conclusions Sodium 12-monoketocholate appears to decrease the intestinal absorption of methotrexate in rats by inhibition of transcellular active transport.