Adequate tumour quinidine levels for multidrug resistance modulation can be achieved in vivo.
The multidrug resistance (MDR) phenotype can be reversed in vitro by a number of agents thought to interact with P-glycoprotein (P-gp). Although plasma levels, adequate for MDR modulation, can be achieved with certain modulators, concern has been expressed that tumour levels may be inadequate due to high plasma protein binding. Mice bearing an MDR-positive human tumour xenograft were injected intraperitoneally with quinidine (150 mg/kg). After 2 h the mean plasma quinidine level was 1.9 micrograms/ml (5.1 mumol/l) and the mean tumour quinidine effective in vitro. Three tumour biopsy specimens were obtained from patients who had received oral quinidine prior to surgery. Plasma and tumour levels were similar and were comparable with those measured in mice. This study should dispel fears of inadequate tumour levels of this and other modulators due to high plasma protein binding and encourage future clinical trials of modulators in MDR-positive human tumours.
Wishart
G C
GC
CRC Department of Medical Oncology, University of Glasgow, Bearsden, U.K.
Plumb
J A
JA
Morrison
J G
JG
Hamilton
T G
TG
Kaye
S B
SB
D000818:Animals; D001943:Breast Neoplasms / Q000097:blood / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011802:Quinidine / Q000032:analysis* / Q000097:blood; D014407:Tumor Cells, Cultured
D011802:Quinidine