Reversal of drug-resistant falciparum malaria by calcium antagonists: potential for host cell toxicity.
Agents capable of reversing multidrug resistance (mdr) in falciparum malaria were investigated for potentiation of chloroquine accumulation and toxicity in a cell culture system. Verapamil, its analog RO11-2933, and desipramine caused a dose-dependent increase in the accumulation of chloroquine (CQ) within human and mouse hepatocytes but not human lung cells. Only those cells in which drug accumulation was enhanced by reversing agents reacted positively for P-glycoprotein (PgP)--the putative mediator of the enhanced drug efflux characteristic of mdr. Clinically achievable concentrations of verapamil (0.4 microM) and desipramine (1 microM) increased CQ accumulation within primary mouse hepatocytes by more than 50%. A well-differentiated normal human cell line (Hep-G2) was killed in media containing a combination of supraphysiological concentrations of CQ and verapamil but survived the same concentrations of either drug alone. Reversing agents may block PgP-mediated drug export from normal tissues as well as from MDR cells. Iatrogenic toxicity resulting from this accumulation of potentially toxic drugs such as CQ within normal cells could complicate the reversal of mdr in vivo.
Watt
G
G
Department of Hematology, Walter Reed Army Institute of Research, Washington, DC.
Long
G W
GW
Grogl
M
M
Martin
S K
SK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002738:Chloroquine / Q000378:metabolism*; D003891:Desipramine / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D006023:Glycoproteins / Q000037:antagonists & inhibitors; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics; D010963:Plasmodium falciparum / Q000378:metabolism*; D011437:Propylamines / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*; D014750:Vincristine / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D011437:Propylamines; D014750:Vincristine; D002738:Chloroquine; C054970:Ro 11-2933; D014700:Verapamil; D003891:Desipramine