Cyclosporin efflux system

Augustijns PF, Bradshaw TP, Gan LS, et al. Evidence for a polarized efflux system in CACO-2 cells capable of modulating cyclosporin A transport. Biochem Biophys Res Commun 1993 197(2) 360-365. 

An alternative explanation to that of the molecular weight threshold of BBB transport is thought to be due to the action of an active efflux system at the BBB. It is proposed that such an active efflux system is p-glycoprotein based (see Sections 1.3.2 and 6.3.4). For example, vinblastine, vincristine, and cyclosporin are all potential substrates for p-glycoprotein. 

Augustijns P, Bradshaw TP, Gan LSL, Henden RW, and Thakker DR. Evidence of a Polarized Efflux System in Caco-2 Cells Capable of Modulating Cyclosporin a Transport. Biochem Biophys Res Commun 1993 197 360-365. 

Pure cholestasis without hepatitis is observed most frequently with contraceptives and 17a-alkylated androgenic steroids, and the mechanism most likely involves interference with hepatocyte canalicular efflux systems for bile salts, organic anions, and phospholipids. The rate-limiting step in bile formation is considered to be the bile salt export pump (BSEP)-mediated translocation of bile salts across the canalicular hepatocyte membrane. Inhibition of BSEP function by metabolites of cyclosporine A, troglitazone, bosentan, rifampicin, and sex steroids is an important cause of drug induced cholestasis (Kullak-Ublick, 2004). 

BMECs have been used to study various aspects of the P-gp-mediated efflux of compounds from the endothelial cells that comprise the BBB. Several examples have demonstrated the usefulness of this system to study polarized efflux via P-gp. For example, the influence of P-gp expressed in brain capillary endothelial cells on the transport of cyclosporin A (388,389), vincristine (381), protease inhibitors (amprenavir, saquinavir, and indinavir) (245,390), rhodamine 123 (211,383), opioid peptides (211,391,392), and the (1-blocking agent bunitrolol (393) have all been determined using this system. 

Several experimental systems to check the inhibition potency of bile add transport have been characterized. Using sandwich-cultured human hepatocytes, bosentan, cyclosporin A, CI-1034 (endothelin-A receptor antagonist), glyburide, erythromycin estolate, and troleandomycin could inhibit the taurocholate efflux to the bile pocket [234]. Moreover, Mita et al. [235] construded NTCP/BSEP double-transfeded cells and some cholestasis-induced compounds inhibited both the NTCP-mediated uptake and the BSEP-mediated efflux of taurocholate. Then, they have found fluorescent bile acids whose transcellular transport was dearly observed, which may be used for the rapid identification of inhibitors of NTCP and BSEP in drug screening process [235]. 

---