PREPARATION, CHARACTERIZATION, AND ANESTHETIC PROPERTIES OF 2-HYDROXYPROPYL-BETA-CYCLODEXTRIN COMPLEXES OF PREGNANOLONE AND PREGNENOLONE IN RAT AND MOUSE
PREPARATION, CHARACTERIZATION, AND ANESTHETIC PROPERTIES OF 2-HYDROXYPROPYL-BETA-CYCLODEXTRIN COMPLEXES OF PREGNANOLONE AND PREGNENOLONE IN RAT AND MOUSE
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DOI：
10.1002/jps.2600841004
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发表时间：
1995-10-01
影响因子：
3.8
通讯作者：
POP, E
中科院分区：
文献类型：
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作者：
BREWSTER, ME;ANDERSON, WR;POP, E
用2-羟丙基-β-环糊精(HP-βCD)增溶孕酮衍生物孕烯醇酮和孕烯醇酮，得到孕酮衍生物的原型制剂。类固醇类化合物的水溶解度随HPβCD浓度的增加而增加，生成线性(A(L))或曲线(A(P))相溶解度曲线。添加少量(0.10%)羟丙基甲基纤维素不能提高孕烯醇酮在HP-βCD中的溶解度，但可使其在HP-βCD中的浓度提高60%以上。小鼠研究发现，虽然孕烯醇酮在HPβCD载体中具有很高的效力，但孕烯醇酮却没有活性。由于孕烯醇酮和孕烯醇酮在结构和物理化学特征上略有不同，数据表明这些衍生物通过特定的受体相互作用，而不是通过非特异性的膜扰动。在孕酮复合体的作用中观察到性别差异，因为静脉注射和静脉注射给药对男性比女性更有效。这些数据与在阿法酮(一种相关的类固醇麻醉剂)的情况下观察到的性别差异有利于雌性动物的情况形成了对比。另一方面，女性在口服时似乎对孕酮复合体的影响更敏感。注射用孕酮对雄性的毒性大于雌性，LD(50)(Iv)分别为355和548 mU/kg。
Prototype formulations of the progesterone derivatives pregnanolone and pregnenolone were prepared by solubilizing the steroids in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). The aqueous solubility of the steroids was increased as a function of HP beta CD concentration generating linear (A(L)) or curvilinear (A(P)) phase-solubility profiles. While the solubility of pregnanolone could not be increased with the addition of water-soluble pharmaceutical polymers, the concentration of pregnenolone in HP beta CD was increased more than 60% by the addition of small amounts (0.10%) of (hydroxypropyl)methylcellulose. Mice studies found that while pregnanolone was highly potent in an HP beta CD vehicle, pregnenolone was devoid of activity. Since pregnenolone and pregnanolone differ marginally in structure and physicochemical profile, the data suggest that these derivatives interact via a specific receptor and not via nonspecific membrane perturbations. Sex differences in the action of the pregnanolone complex was observed in that parenteral (iv and ip) drug administration was more effective in males than females. These data are in contrast to observations made in the case of alfaxalone, a related steroid anesthetic, in which the sex difference favored female animals. On the other hand, females appeared to be more sensitive to the effects of the pregnanolone complex when administered orally. Finally, parenteral pregnanolone was more toxic to males than females with LD(50) (iv) values of 355 and 548 mu mol/kg, respectively.