Endocrine Abstracts (2011) 26 P72

Distribution of mitotane and its two metabolites in liproprotein fractions of patients with adrenocortical carcinoma

Y Cazaubon1,2, S Broutin2, A Seck1,2, H Remy3,5, F Lemare3, J M Bidart4, C Chougnet5, S Leboulleux5, M Schlumberger5, E Baudin5 & A Paci1,2

1UMR 8203 Institut Gustave Roussy, Villejuif, France; 2Pharmacology and Drug Analysis Department, Villejuif, France; 3Clinical Pharmacy Department, Villejuif, France; 4Biology and Biopathology Department, Villejuif, France; 5Nuclear Medecine and Endocrine Cancerology Department, Villejuif, France.

Introduction: Adrenocortical carcinoma (ACC) is a rare tumor of the adrenals with poor prognosis (survival rate for metastatic patients <15% at 5 years). Mitotane (o,p′-DDD) is the main therapeutic option with up to 66% objective response rates in patients with serum levels between 14 and 20 mg/l. Its two main metabolites are o,p′-DDA and o,p′-DDE which plasma levels are not correlated to therapeutic response. Mitotane is a lipophilic drug that accumulates in lipoproteins and induces hypercholesterolemia by activation of HMGCoA reductase. Looking for predictive/prognostic markers of response we assessed the distribution of o,p′-DDD and its metabolites in lipoprotein fractions of ACC patients.

Materials and methods: Levels of o,p′-DDD, o,p′-DDA and o,p′-DDE were measured using HPLC-UV method after liquid-liquid extraction with p,p′-DDE as internal standard. Lipoprotein fractions from plasma of ACC patients treated with mitotane were obtained by differential ultracentrifugation process.

Results: We developed and validated an HPLC-UV method. The extraction yields of o,p′-DDD, o,p′-DDA and o,p′-DDE are 75, 73 and 38% respectively. This method is linear, precise, accurate and no matrix effect was observed (<2%). The method of separation of lipoproteins by differential ultracentrifugation allowed us isolating VLDL, LDL and the mixture HDL-proteins. Analyses in a few plasma patients showed a major distribution of o,p′-DDA in HDL (99%) while o p′-DDD and o,p′-DDE were mainly measured in HDL (>70%), partially in LDL (12–25%) and barely in VLDL (<5%).

Conclusion: This work allowed us to define conditions for the study of o,p′-DDD, o,p′-DDA and o,p′-DDE distribution in the different lipoprotein fractions. The preliminary results showed a different distribution profile for o,p′-DDA. The perspectives of this study are multiple: evaluation of lipoprotein distribution over time in a large cohort of patients; dyslipoprotidemia impact; relationship between o,p′-DDD, o,p′-DDA and o,p′-DDE lipoprotein plasma levels and therapeutic response.

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