ABSTRACT
Title
Pharmacogenetic determinants of mitotane pharmacokinetics in adrenocortical cancer patients.
Authors
F. De Martino1, S. De Francia1, A. D’Avolio2, E. Pirro1, F. Piccione1, J. Cusato2, A. Berruti3, M. Terzolo4, F. Di Carlo2.
1Clinical Pharmacology of San Luigi Hospital, University of Turin;
2Clinical Pharmacology and Pharmacogenetics of Amedeo di Savoia Hospital, University of Turin;
3Division of Medical Oncology of San Luigi Hospital, University of Turin.
4Division of Internal Medicine-Endocrinology of San Luigi Hospital, University of Turin.
1Clinical Pharmacology of San Luigi Hospital, University of Turin;
2Clinical Pharmacology and Pharmacogenetics of Amedeo di Savoia Hospital, University of Turin;
3Division of Medical Oncology of San Luigi Hospital, University of Turin.
4Division of Internal Medicine-Endocrinology of San Luigi Hospital, University of Turin.
Abstract
Mitotane (o,p’-DDD) is the reference agent for treatment of adrenocortical carcinoma (ACC), a rare endocrine disease with a poor prognosis, characterized by a reported incidence of 1-2 per million population per year and a 5-year survival less than 50%. It’s known [1,2]that mitotane antitumor efficacy is observed with plasma concentrations >14mg/l while toxicities are usually associated with concentrations >20mg/l. Mitotane levels correlate with assumed dose and clinical response, although wide differences in concentrations are reached in some patients receiving the same dose. Mitotane metabolism is demonstrated to be mainly mediated by CYP 2B1, 3A1, 2B6, and 3A4. Aim of this retrospective study was to assess the potential impact of pharmacogenetic (PG) variability on plasmatic pharmacokinetics (PK) of mitotane and on clinical responses of patients. To this aim we used stored blood residual samples of ACC patients who received mitotane and were monitored in the last 5 years at San Luigi Hospital. DNA has been extracted from whole blood and PG analysis was performed with Real Time-PCR instrument, using validated methods. Candidate genes for PG analysis included MDR1, CYP3A4, CYP3A1, CYP2B1, CYP2B6, HNF4, PXR, CAR. Drugs plasma troughlevels have been determined by HPLC-UV validated method [3] and clinical response was assessed by evaluation of hemochrome and biochemical data.
[1] H. van Slooten et al. Eur. J. Cancer Clin. Oncol. 20, 47 (1984).
[2] E. Baudin et al. Cancer. 92, 1385 (2001).
[3] S. De Francia et al. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 837, 69 (2006).
[1] H. van Slooten et al. Eur. J. Cancer Clin. Oncol. 20, 47 (1984).
[2] E. Baudin et al. Cancer. 92, 1385 (2001).
[3] S. De Francia et al. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 837, 69 (2006).