Benecke R, Keller E, Vetter B, de Zeeuw R A
Section Biosciences, University of Leipzig, FRG.
Eur J Clin Pharmacol. 1991;41(3):259-61. doi: 10.1007/BF00315440.
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 micrograms/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 micrograms/ml for several weeks may lead to relapses, whereas DDD-levels over 10 micrograms/ml gave rise to side effects. On the other hand, o,p'-DDE seemed inactive at levels up to 4 micrograms/ml in plasma.
米托坦（邻，对'-滴滴滴）可用于治疗各种肾上腺皮质疾病，如库欣综合征，但通常每天6 - 8克的剂量常伴有严重不良反应。本文报告了两名库欣病患者分别在8年和5年期间使用低得多剂量的邻，对'-滴滴滴（每天0.5 - 2克）的结果，同时监测母体药物及其主要代谢产物邻，对'-滴滴伊的血浆水平。很明显，邻，对'-滴滴滴和邻，对'-滴滴伊由于其高亲脂性而有在体内强烈蓄积的倾向。因此，剂量方案的改变在血浆水平反映出来之前有很长的延迟时间，一旦开始增加或减少，必须小心避免造成超调。邻，对'-滴滴滴的稳态血浆水平在5 - 10微克/毫升之间似乎足以诱导并维持疾病缓解，此时血浆和尿液中的皮质醇水平正常。持续数周低于5微克/毫升的滴滴滴水平可能导致复发，而高于10微克/毫升的滴滴滴水平会引起副作用。另一方面，血浆中邻，对'-滴滴伊水平高达4微克/毫升时似乎无活性。
