Ll. Horstman et al., DANAZOL DISTRIBUTION IN PLASMA AND CELL-MEMBRANES AS RELATED TO ALTERED CELL PROPERTIES - IMPLICATIONS FOR MECHANISM, American journal of hematology, 50(3), 1995, pp. 179-187
Concentrations of danazol in patient plasma and red blood cells (RBC)
were assayed over a 6-month period in 75 patients on danazol therapy u
sing a high-pressure liquid chromatography (HPLC) method more reliable
than previous radioimmunoassay (RIA) methods, It was found that plasm
a danazol rose regularly for 15 days after the beginning of treatment,
reaching a steady state plateau of 175 +/- 76 ng/ml in 20 patients on
normal dose, and less for lower dose schedules. After stopping danazo
l, concentrations declined to near zero in a similar time frame. RBC c
oncentrations on a packed volume basis were similar to plasma levels.
However, the membrane ghosts of RBC contained about 50% of the total R
BC danazol, implying about 100-fold higher concentration in membranes
than in plasma, Similar distributions were obtained in vitro with both
RBC and platelets, and were confirmed by 14-C-labeled danazol, These
findings tend to support the hypothesis that the benefits of danazol i
n immune disorders may be attributable in part to its intercalation in
the lipid bilayer of the plasma membrane, altering antigen/receptor e
xpression to modulate immune reactions. This hypothesis was first sugg
ested when it was observed that the RBC of patients on danazol therapy
showed morphological changes and increased resistance to osmotic lysi
s. It was later shown that danazol in vitro reduces binding of autoant
ibodies, and protects against complement-mediated lysis, suggesting di
rect action of danazol on the membranes, This hypothesis is discussed,
and danazol's effect in protecting against complement-mediated lysis
is described. (C) 1995 Wiley-Liss, Inc.