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

Abstract

Progesterone is metabolized by ring-A reduction with subsequent oxidoreduction to 3α-hydroxy-5α-dihydroprogesterone (3α-OH-5α-DHP), a naturally occuring metabolite that has been shown to enhance [ 3H]flunitrazepam ([ 3H]FNZ) binding. Medroxy-progesterone 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, 3α-OH-5α-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 statis 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.