Biliary excretion of estradiol-17β-glucuronide in the rat

Estradiol-17β-glucuronide (E₂17G) is a cholestatic agent and is considered to be related to the pathogenesis of intrahepatic cholestasis of pregnancy. In the current study, we examined the mechanism of the biliary excretion of E₂17G and estradiol metabolites in rats. Biliary excretion of tracer doses of [³H]estradiol-17β-glucuronide and [¹⁴C]estradiol or [³H]taurocholate and [¹⁴C]vinblastine, a P-glycoprotein (P-GP) substrate, intravenously administered as a bolus to bile-drained control rats or EHBR was studied. Biliary excretion of E₂17G and estradiol metabolites in EHBR was markedly delayed. Analyses of biliary metabolites after estradiol injection showed less polar conjugates in EHBR. In contrast, the excretion of taurocholate and vinblastine (VLB) was only slightly delayed in EHBR. Although phenothiazine treatment to induce the expression of P-GP increased biliary vinblastine excretion, it did not affect biliary excretion of a tracer dose of [³H]estradiol-17β-glucuronide. However, phenothiazine treatment inhibited the cholestasis induced by E₂17G infused at the rate of 0.075 μmol/min/100 g for 20 minutes and increased biliary E₂17G excretion. Sulfobromophthalein infusion (0.2 μmol/min/100 g body weight) markedly inhibited the biliary excretion of E₂17G and estradiol metabolites, whereas dibromosulfophthalein (DBSP) at the same infusion rate had no effect. These findings indicate that E₂17G is excreted into bile by a canalicular organic anion carrier for sulfobromophthalein (BSP), not for DBSP, under physiological conditions, and that P-GP influences E₂17G excretion only at a high dose.