Plasma level monitoring of mitotane (o,p'-DDD) and its metabolite (o,p'-DDE) during long-term treatment of cushing's disease with low doses |
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Authors: | R. Benecke E. Keller B. Vetter R. A. de Zeeuw |
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Affiliation: | (1) Section Biosciences, Pediatric Clinic, Leipzig, FRG;(2) Endocrine Department, Pediatric Clinic, Leipzig, FRG;(3) Clinic for Anaesthesiology and Intensive Care, University of Leipzig, Leipzig, FRG;(4) Department of Analytical Chemistry and Toxicology, University Centre for Pharmacy, Groningen, The Netherlands |
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Abstract: | Summary. Mitotane (o,p'-DDD) can be used for the treatment of various adrenocortical diseases such as Cushing's syndrome, but the usual doses of 6–8 g per day are often associated with severe adverse effects.This paper reports the results of much lower doses of o,p'-DDD (0.5–2 g per day) in two patients with Cushing's disease over periods of 8 and 5 years, respectively, under concomitant monitoring of the plasma levels of the parent drug and its major metabolite, o,p'-DDE.It became apparent that o,p'-DDD and o,p'-DDE have a strong tendency to accumulate in the body due to their high lipophilicity. As a consequence, changes in dose regimens had long lag times before they were reflected in plasma levels and once an increase or decrease had started one had to be careful not to cause overshoot.Steady state plasma levels of o,p'-DDD between 5–10 g/ml appeared sufficient to induce and to maintain remission of the disease, which was accompanied with normal cortisol levels in plasma and urine. DDD-levels below 5 g/ml for several weeks may lead to relapses, whereas DDD-levels over 10 g/ml gave rise to side effects. On the other hand, o,p'-DDE seemed inactive at levels up to 4 g/ml in plasma. |
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Keywords: | Cushing's disease Mitotane o,p'-DDD long term treatment plasma monitoring adverse effects |
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