Cancer Chemother Pharmacol (1995) 36:335-340 9 Springer-Verlag 1995 Odalys Gonzalez 9 Tina Colombo Maurizio De Fusco 9 Luigi Imperatori Massimo Zucchetti 9 Maurizio D'Incalci Changes in doxorubicin distribution and toxicity in mice pretreated with the cyclosporin analogue SDZ PSC 833 Received: 18 August 1994/Accepted: 9 November 1994 Abstract SDZ PSC 833 (PSC 833) is a cyclosporin A analogue that is under clinical investigation in com- bination with doxorubicin (Dx) or other anticancer agents as a type-1 multidrug resistance (MDR-1)- reversing agent. The present study was focused on the effects of PSC 833 on the distribution and toxicity of Dx in non-tumor-bearing CDF1 male mice. Mice were given PSC 833 i.p. at 30 min before i.v. Dx treatment. Dx levels were determined by a high-performance liquid chromatography (HPLC) assay at different times during a 72-h period following Dx treatment in the serum, heart, intestine, liver, kidney, and adrenals of mice. In all tissues, Dx area under the concentration- time curve (AUC) values were much greater in mice receiving 10mg/kg Dx in combination with 12.5 or 25 mg/kg PSC 833 than in mice receiving Dx alone. The highest increase in Dx concentrations was found in the intestine, liver, kidney, and adrenals. Lower, albeit significant, differences were found in the heart. PSC 833 did not appear to influence either urinary or fecal Dx elimination or Dx metabolism to a great extent. Doses of PSC 833 devoid of any toxicity potentiated the acute and delayed toxicity of Dx dramatically. The mecha- nism responsible for this enhanced toxicity has not yet been elucidated but is likely to be related to an in- creased tissue retention of Dx due to inhibition of the P-glycoprotein (Pgp) pump by PSC 833, as has recently been proposed for cyclosporin A. Key words MDR 9 Pgp 9 SDZ PSC 833 Abbreviations MDR Multidrug resistance 9 mdr-1 gene multidrug resistance-1 gene. PgP P-glycoprotein 9 PSC O. Gonzalez 9 T. Colombo 9 M. De Fusco - L. Imperatori 9 M. Zucchetti 9 M. D'Incalci (~) Laboratory of Cancer Chemotherapy, Mario Negri Institute for Pharmacological Research, Via Eritrea 62, 1-20157 Milan, Italy 833 SDZ PSC 833 9 Dx doxorubicin 9 HPLC high- performance liquid chromatography- AUC area under the concentration-time curve Introduction The best-characterized mechanism of resistance to an- ticancer agents is related to expression of the mdr-1 gene encoding P-glycoprotein (Pgp). Pgp is a mem- brane-bound transport protein that acts as an energy pump to increase the efftux and reduce the intracellular retention of several structurally unrelated drugs such as anthracyclines, vinca alkaloids, podophyllotoxins, ac- tinomycin D, taxol, and trimetrexate [11,17,18, 23, 31]. Several compounds have been reported to be capable of inhibiting Pgp, thus reversing the resistance mechanism. One of the most interesting multidrug res- istance (MDR)-reversing agents is cyclosporin A. It can reverse resistance to doxorubicin (Dx) and other drugs transported by Pgp at concentrations that can be achieved in vivo at nontoxic doses [14, 26, 29]. Pgp has also been found to be expressed in normal tissues [13, 28], suggesting that cyclosporin A, as well as other reversal agents, increase the sensitivity of nonmalignant tissues to antineoplastic drugs, thereby increasing the toxicity of the drugs and diminishing their therapeutic index. In mice and rats, cyclosporin A causes a signifi- cant increase both in the levels of Dx measured in several types of normal tissue [8] and in Dx toxicity. Recently, a cyclosporin A analogue, SDZ PSC 833 (PSC 833), which is a potent MDR-reversing agent without the immunosuppressive activity of cyclosporin A, was identified [15, 16, 20, 30]. PSC 833 is under early clinical investigation in combination with Dx or etoposide [6, 12, 22, 25]. In the present study we evalu- ated whether PSC 833 could change the distribution, metabolism, elimination, and toxicity of Dx in normal mice.