Pharmacologic interactions between the resistance‐modifying cyclosporine sdz psc 833 and etoposide (VP 16–213) enhance In Vivo cytostatic activity and toxicity

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Abstract
Cyclosporin A reverses multidrug resistance (MDR) and increases the in vivo cytostatic activity and toxicity of the anticancer agent etoposide (VP 16–213). SDZ PSC 833 (PSC 833), a non‐immunosuppressive, non‐toxic cyclosporin and very active modifier of P‐gp 170‐mediated MDR, elicits similar effects when administered with adriamycin. The underlying mechanisms, however, are not yet understood. The present pharmacological interaction study with PSC 833 and VP 16–213 was carried out to reveal the nature of this enhancement of cytostatic activity and toxicity. Rats pre‐treated with either PSC‐833 or solvent received a single dose of VP 16–213. Plasma levels of VP 16–213 were measured by high‐performance liquid chromatography (HPLC). The resulting increase in cytostatic activity and toxicity of VP 16–213 mediated by PSC 833 was paralleled by marked changes in the pharmacokinetic parameters of VP 16–213 in vivo. Bioavailability and blood levels of VP 16–213 were significantly increased 30 min after administration if PSC 833 had been given before. The disappearance rate of VP 16–213 from the intravascular compartment was considerably slowed down by PSC 833. In drug‐sensitive xenografts of human colon carcinoma, the PSC‐833‐induced pharmacologic changes in vivo could be counteracted by dose reduction of VP 16–213 while a full therapeutic potential was maintained. Doses of VP 16–213, 1.5 to 2 times smaller, combined with PSC 833, were as effective in terms of tumor‐growth inhibition as the maximum tolerated dose of VP 16–213 alone. Thus, pharmacologic interactions between PSC 833 or other resistance modifiers and VP 16–213 and other cytostatic agents require careful attention if they are to be used in humans to overcome MDR.

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