McAuley J W, Kroboth P D, Stiff D D, Reynolds I J
Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, PA 15261.
Pharmacol Biochem Behav. 1993 May;45(1):77-83. doi: 10.1016/0091-3057(93)90089-c.
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.
孕酮通过A环还原进行代谢，随后经氧化还原生成3α-羟基-5α-二氢孕酮（3α-OH-5α-DHP），这是一种天然存在的代谢产物，已被证明可增强[3H]氟硝西泮（[3H]FNZ）结合。醋酸甲羟孕酮（MPA）是一种常用的孕激素制剂，是一种合成的孕酮衍生物，其代谢特征与孕酮相似。在本研究中，研究了MPA及其A环还原代谢产物DHMPA和THMPA对[3H]FNZ结合的影响。虽然已知的特异性[3H]FNZ结合调节剂在冷冻和新鲜大鼠皮质组织中显示出预期的效果，但3α-OH-5α-DHP仅在新鲜而非冷冻组织中增强[3H]FNZ结合。DHMPA和THMPA均不影响结合，而MPA可使[3H]FNZ结合部分抑制40%。此外，使用了五种测试药物来评估性别和激素状态对[3H]FNZ结合的影响。性别和激素状态均不影响结合。因此，孕酮而非MPA的A环还原代谢产物可增强[3H]FNZ结合。这些体外研究结果的临床意义目前正在研究中。
