Caenorhabditis elegans: Modest increase of susceptibility to ivermectin in individual P-glycoprotein loss-of-function strains

P-glycoproteins (Pgps) are members of the ABC transporter superfamily and are involved in detoxification mechanisms of single- and multicellular organisms. Their importance for survival of organisms in the presence of harmful drug concentrations has been widely studied in cancer cells but Pgp-dependent drug resistance of parasites has also been demonstrated. Ivermectin (NM), a widely used anthelmintic in human and veterinary medicine, is a known substrate at least of mammalian Pgps and resistance against IVM is proposed to be associated with Pgps. The consequences of loss of Pgp function for the development of the model nematode Caenorhabditis elegans were analysed in the presence of IVM. Either strains missing only a single Pgp were used or Pgp activity generally was inhibited using verapamil (VPL). Loss-of-function of individual Pgp resulted in a statistically significant increase in IVM susceptibility in terms of impaired development with decreases in EC50 values between 1.5- and 4.3-fold. Absence of seven Pgps resulted in a higher impact on IVM susceptibility of C elegans since it resulted in EC50 values decreased by 2.4- to 4.3-fold. This increase in IVM susceptibility was even more pronounced than that observed when Pgp function was blocked in general by VPL (approximately 2.5-fold). This study demonstrates clearly that Pgps are of importance for IVM detoxification in the model organism C elegans and that some Pgps obviously have a higher impact than others. (C) 2013 Elsevier Inc. All rights reserved.