Kinetic parameters for reversal of the multidrug pump as measured for drug accumulation and cell killing.
We determined the kinetic parameters that describe the effect of 20 different modulators of the multidrug resistance pump on the reversal of cytotoxin accumulation in a resistant strain of P388 leukemia cells (P388/ADR), and on the reversal of cell killing for these cells. When measured by a direct comparison of the amplitude of the pertinent protocol (accumulation or cell killing), the Ki for reversal of accumulation was generally some four or five times larger than that for reduction of cytotoxicity. We showed that this was only an apparent discrepancy, since a full theoretical analysis of the two protocols allowed the intrinsic Ki to be obtained for the two procedures and these computed Ki values were then almost identical. We found that for six of the modulators studied (namely, cyclosporin A, quinidine, dipyridamole, propafenone, mefloquine, tamoxifen) the extent of pump reversal should be better than 90% at tolerated plasma levels culled from the literature.
Lan
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LB
Biochemistry Department, Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel.
Ayesh
S
S
Lyubimov
E
E
Pashinsky
I
I
Stein
W D
WD
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D002470:Cell Survival / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology; D003603:Cytotoxins / Q000494:pharmacology; D003630:Daunorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000502:physiology; D006801:Humans; D011405:Propafenone / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology; D014747:Vinblastine / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D003603:Cytotoxins; D014268:Trifluoperazine; D014747:Vinblastine; D011405:Propafenone; D016572:Cyclosporine; D003630:Daunorubicin