Cyclosporins are potent tools to inhibit several primary-active,
ATP-dependent export carriers. This has been demonstrated in membrane vesicle transport assays for CsA and for its non-immunosuppressive analog
PSC 833. Inhibition in the low micromolar and in the nanomolar concentration range is shown for the three distinct
ATP-dependent export carriers in the liver canalicular membrane mediating the secretion into bile of
leukotrienes (
LTC4, other cysteinyl
leukotrienes, and related conjugates),
bile salts (
taurocholate), and amphiphilic, mostly cationic substances (
daunorubicin and other
P-glycoprotein substrates). Competitive inhibition by
cyclosporins is most potent for
ATP-dependent
taurocholate transport with Ki values of 0.2 and 0.6 microM for CsA and
PSC 833, respectively. This inhibition is in agreement with in vivo studies in the rat demonstrating a block at the canalicular membrane in the hepatobiliary elimination of labeled
taurocholate. The data suggest that
cholestasis, as a side effect during CsA
therapy, is largely due to inhibition of the
ATP-dependent
bile salt export carrier in the canalicular membrane. Inhibition by
cyclosporins is less effective with respect to
ATP-dependent
leukotriene transport, both during biosynthetic release from
mastocytoma cells and during hepatobiliary excretion. The Ki values for the former were 4.5 and 30 microM, and the Km/Ki ratios only 0.015 and 0.002 for CsA and
PSC 833, respectively. Distinct transporters are inhibited by the
cyclosporins with different potency and structurally modified
cyclosporins may serve to induce preferential inhibition of a selected transporter. This is illustrated by the inhibition of the multidrug export carrier with
daunorubicin as substrate using
PSC 833 as inhibitor with a Ki value of 0.3 microM in an in vitro membrane transport system.