Among the compounds endowed with the capacity to reverse the
P-glycoprotein (Pgp)-mediated multidrug resistance of
cancer cells, a powerful agent was found to be the
cyclosporin D derivative
SDZ PSC 833. After in vivo treatment with
SDZ PSC 833, mice showed a decreased tolerability to
cyclosporin A (CsA), but also to
ivermectin, a widely used polycyclic
lactone pesticide of Streptomyces avermitilis origin. The sequels were suggestive of CsA- or
ivermectin-induced central nervous system dysfunction; they were interpreted as caused by the neutralization of the Pgp at the blood-brain barrier level, implying that CsA and
ivermectin were Pgp substrates. CsA was already known to display both Pgp substrate and Pgp inhibitor properties. It now appears that
ivermectin may also inhibit Pgp function. When compared in short-term assays for Pgp function inhibition, which measure the restoration of the retention of two Pgp probes in multidrug-resistant (MDR) cells to their parental (Par) cell levels,
ivermectin appeared only a few fold weaker that
SDZ PSC 833 in the case of murine monocytic
leukemia MDR-P388 cells and nearly as active as
SDZ PSC 833 in the case of human
lymphocytic leukemia MDR-CEM cells. Therefore, like CsA or
FK-506,
ivermectin may also be a substrate and an inhibitor of Pgp.