Differential modulation of CACO‐2 mediated transport of rhodamine‐123 by 17‐beta estradiol, progesterone and testosterone

Steroidal hormones may play a significant role in the modulation of gender differences in pharmacokinetics. P‐glycoprotein (P‐gp), an ATP‐binding cassette transport protein, can transport a variety of hormones, including some steroid hormones. Although interactions between progesterone (P) and P‐gp have been reported, little is known about interactions with 17‐β estradiol (E 2 ) or testosterone (T). We used an in vitro model of intestinal drug transport to assess the effects of steroid hormones on rhodamine‐123 (Rho‐123) transport. E 2 treatment (2.5ηM to 25μM) consistently resulted in approximately 20% or greater elevation of AUC 0–120 values (AU*min) when compared to control (C) (C: 8,830, 25μM E 2 : 11,566). Co‐administration of tamoxifen or Gö6983 (a protein kinase C inhibitor), at concentrations that do not alter Rho‐123 transport, inhibit the E 2 dependent activation. Unlike E 2, 17‐α ethinyl estradiol, an estrogenic component of many oral contraceptives, demonstrates no effect on Rho‐123 transport. Conversely, T and P demonstrated significant inhibition of AUC 0–120 values at concentrations within the micro‐molar range (C: 10,359, 25μM P: 4,315, C: 8,787, 25μM T: 3,886). Linear regression analysis of these data confirms these interactions. These data suggest that hormonal modulation of P‐gp may be an important factor in determining gender specific alterations in the absorption, distribution, metabolism, and elimination of P‐gp substrates, and should be explored further. Clinical Pharmacology & Therapeutics (2004) 75 , P87–P87; doi: 10.1016/j.clpt.2003.11.331