Kuhnz W, Fritzemeier K H, Hegele-Hartung C, Krattenmacher R
Research Laboratories, Schering Aktiengesellschaft, Berlin, Germany.
Contraception. 1995 Feb;51(2):131-9. doi: 10.1016/0010-7824(94)00019-s.
The progestational activity of norgestimate (NORG), levonorgestrel-oxime (LNG-oxime) and levonorgestrel (LNG) were compared in a pregnancy maintenance study in rats. The compounds were administered subcutaneously to pregnant rats at several doses, blood samples were collected repeatedly, and the concentration of LNG was measured in these samples. It could be demonstrated that following the administration of NORG and LNG-oxime, LNG was a major metabolite present in the serum. The pharmacological response in rats treated with NORG and LNG-oxime could be related to the systemic exposure of these animals to metabolically derived LNG. Thus, both NORG and LNG-oxime can be regarded as pro-drugs of LNG, the latter being almost exclusively responsible for the pharmacological activity of both pro-drugs. This notion was further supported by studies on the comparative binding affinity of these compounds to rabbit and human progesterone receptor (PR). LNG exhibited the highest binding affinity of the compounds studied. Relative binding affinity (RBA) values of LNG using progesterone as reference (100%) were found to be 125% for rabbit PR (rPR), 143% for human uterine PR (hPR) and 125% for recombinant hPR, respectively. In contrast to LNG, NORG exhibited only a low affinity to the PR, which is documented by RBA values of 1.2% for rPR, 3.2% for uterine hPR and 9% for recombinant hPR. The corresponding values of LNG-oxime were 30% (rPR), 20% (uterine hPR) and 18% (recombinant hPR), respectively. Thus, the combined experimental evidence of the present study does not support the view of NORG being a progestogen on its own as has been suggested by others.
在一项大鼠妊娠维持研究中，比较了诺孕酯（NORG）、左炔诺孕酮肟（LNG-肟）和左炔诺孕酮（LNG）的孕激素活性。以几种剂量对怀孕大鼠进行皮下给药，反复采集血样，并测定这些样品中LNG的浓度。结果表明，给予NORG和LNG-肟后，LNG是血清中的主要代谢产物。用NORG和LNG-肟处理的大鼠的药理反应可能与这些动物对代谢产生的LNG的全身暴露有关。因此，NORG和LNG-肟都可被视为LNG的前体药物，后者几乎完全负责这两种前体药物的药理活性。这些化合物与兔和人孕激素受体（PR）的比较结合亲和力研究进一步支持了这一观点。在所研究的化合物中，LNG表现出最高的结合亲和力。以孕酮为参照（100%），LNG对兔PR（rPR）的相对结合亲和力（RBA）值为125%，对人子宫PR（hPR）为143%，对重组hPR为125%。与LNG相反，NORG对PR仅表现出低亲和力，rPR的RBA值为1.2%，子宫hPR为3.2%，重组hPR为9%，证明了这一点。LNG-肟的相应值分别为30%（rPR）、20%（子宫hPR）和18%（重组hPR）。因此，本研究的综合实验证据不支持其他人所提出的NORG本身是一种孕激素的观点。
