Pharmacokinetic and pharmacodynamic studies on cisplatin in mice and men

University dissertation from Anders Johnsson MD, Dept of Oncology, University Hospital, S-21 85 Lund, Sweden

Abstract: Methodological tools for studies of the cytostatic agen cisplatin (CDDP) were explored and applied to elucidate various aspects of pharmacokinetics, drug distribution, chemomodulation and pharmacodynamics. An immunohistochemical assay for analysis of CDDP-DNA adducts, i.e. the drug in its probable target position, was modified to allow quantitation with computerized image analysis. The methodological sources of error were estimated. We found the method to be feasible for comparing samples of the same tissue type, stained in the same batch and preferrably measured by one observer on one occasion. The pharmacokinetics were studied as platinum (Pt) and CDDP-DNA adducts in nude mice. The highest tissue concentration was noted in kidney at 15 min. A biphasic elimination of Pt was observed in most sample types and the terminal half-life was similar (55h-76h) in whole-blood, serum, kidney, liver and testis. In brain the pharmacokinetics differed with a gradual accumulation during the study period of 7 days. Peak adduct levels were reached between 30 min and 4h. Each tissue type had its specific adduct staining pattern. With escalating CDDP doses there was a linear increase in both Pt concentrations and CDDP-DNA adducts including tumor. There were also good correlations between serum-Pt, tissue levels of Pt and adducts, respectively. Heterogeneities in the intratumoral drug distribution were described and a model was presented for investigating the potential influence of vascularization and cell proliferation on intratumoral adduct distribution by using different immunohistochemical stainings of parallel sections. A weak correlation was found between adducts and proliferation, which might indicate that drug uptake and adduct formation is increased in proliferating cells. The antifungal agent amphotericin B was given to glioma-bearing rats with the purpose of enhancing the cytotoxicity of CDDP. The combined treatment resulted in excessive nephrotoxicity and in increase levels of CDDP-DNA adducts on kidneys. This indicates that nephrotoxicity is related to adduct formation in kidneys. It also shows that adduct analysis can be a valuable tool for assessing the mechanisms of interaction between CDDP and modulation agents. Ten patients were studies during the first cycle of CDDP-based chemotherapy. With limited-sampling and a population approach useful pharmacokinetic information was obtained. CDDP-DNA adducts in lymphocytes and buccal cells showed different kinetic profiles, possibly due to differences in cell turn-over. Renal damage, studied in terms of urinary protein excretion, was first displayed as tubular damge and later as impaired glomerular barrier function. Significant correlations were found between tubular dysfunction and pharmacokinetic parameters. These results could be the basis for further pharmacodynamic studies aiming towards individualized dose adaptation for cancer chemotherapy.

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