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.