Modulation of [3H]flunitrazepam binding by natural and synthetic progestational agents.

Progesterone is metabolized by ring-A reduction with subsequent oxidoreduction to 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-5 alpha-DHP), a naturally occurring metabolite that has been shown to enhance [3H]flunitrazepam ([3H]FNZ) binding. Medroxyprogesterone acetate (MPA), a commonly prescribed progestational agent, is a synthetic progesterone derivative that has a metabolic profile similar to that of progesterone. In this study, the effects of MPA and its ring-A reduced metabolites DHMPA and THMPA on [3H]FNZ binding were investigated. While known modulators of specific [3H]FNZ binding demonstrated expected effects in frozen and fresh rat cortical tissue, 3 alpha-OH-5 alpha-DHP enhanced [3H]FNZ binding only in fresh, not frozen, tissue. Neither DHMPA nor THMPA affected binding, while MPA partially inhibited [3H]FNZ binding by 40%. In addition, five test drugs were used to assess the effect of gender and hormonal status on [3H]FNZ binding. Neither gender nor hormonal status influenced binding. Thus, ring-A reduced metabolites of progesterone but not of MPA enhance [3H]FNZ binding. The clinical implications of these in vitro results are currently under investigation.