Kühn-Velten W N, Herzog A G, Müller M R
Institut für Physiologische Chemie II, Heinrich-Heine-Universität, Düsseldorf, F.R.G.
Eur J Pharmacol. 1990 May 31;181(1-2):151-5. doi: 10.1016/0014-2999(90)90258-8.
The possibility of direct inhibition of testicular endocrine function by carbamazepine, phenytoin, or valproate was tested using the rat Leydig cell model in vitro in order to find whether such an effect could contribute to the reduction of plasma free testosterone levels reported in male patients who take antiepileptic medications. With maximally stimulating concentrations of human choriogonadotropin (hCG) or cyclic AMP, testosterone formation was inhibited by 50% in the presence of 40 microM carbamazepine, 350 microM phenytoin, or greater than 1 mM valproate. With submaximally stimulating concentrations of hCG, leading to physiological testosterone secretion rates, half-maximal inhibition occurred in the presence of 15 microM carbamazepine, 180 microM phenytoin, or 900 microM valproate. Only the values for carbamazepine were in the clinically therapeutic range. Further investigation revealed that carbamazepine acted primarily at a target between cyclic AMP formation and cholesterol conversion to androgens. In contrast, phenytoin acted by competitive interaction at the cytochrome P450XVII which converts progesterone to androgens. Valproate had by far the lowest potential to generate adverse effects in this endocrine system.
为了探究卡马西平、苯妥英或丙戊酸盐是否会直接抑制睾丸内分泌功能，从而导致服用抗癫痫药物的男性患者血浆游离睾酮水平降低，研究人员使用大鼠睾丸间质细胞模型进行了体外试验。在人绒毛膜促性腺激素（hCG）或环磷酸腺苷（cAMP）的最大刺激浓度下，40微摩尔/升的卡马西平、350微摩尔/升的苯妥英或大于1毫摩尔/升的丙戊酸盐存在时，睾酮生成被抑制了50%。在hCG的亚最大刺激浓度下，即导致生理性睾酮分泌速率时，15微摩尔/升的卡马西平、180微摩尔/升的苯妥英或900微摩尔/升的丙戊酸盐存在时，出现了半数最大抑制。只有卡马西平的值处于临床治疗范围内。进一步研究表明，卡马西平主要作用于环磷酸腺苷生成与胆固醇转化为雄激素之间的靶点。相比之下，苯妥英通过与将孕酮转化为雄激素的细胞色素P450XVII发生竞争性相互作用发挥作用。在这个内分泌系统中，丙戊酸盐产生不良反应的可能性迄今为止是最低的。
