Coleman M D, Smith S N, Kelly D E, Kelly S L, Seydel J K
Department of Pharmaceutical Sciences, Aston University, Birmingham, UK.
J Pharm Pharmacol. 1996 Sep;48(9):945-50. doi: 10.1111/j.2042-7158.1996.tb06008.x.
Three metabolizing systems (rat, heterologously expressed CYP3A4 and human liver) were used to evaluate 12 analogues of dapsone (4,4'diaminodiphenylsulphone) in-vitro. Methaemoglobin formation in a two-compartment and cytotoxicity in a single-compartment model were studied using human erythrocytes and neutrophils, respectively, as target cells. In the two-compartment system using rat microsomes as a generating system and methaemoglobin as an endpoint, the least potent methaemoglobin formers tested were the 2-methyl-4-propylamino (AXDD14), 2-hydroxy-4-4'amino (ABDD5) derivatives and a sulphone/trimethoprim derivative (K-130). Dapsone itself, a 2-methoxy-4-ethylamino (W10) and a 2-hydroxyl-4-ethylamino compound (ABDD39) were the most toxic. In the single-compartment cytotoxicity test using rat microsomes, AXDD14 was again among the least toxic, as was a 2-methyl 4-cyclopentyl derivative (AXDD17) and surprisingly ABDD39. The most cytotoxic compounds again included dapsone itself as well as two 2-trifluoromethyl derivatives. The only significant methaemoglobin formation and cytotoxicity shown with the heterologously expressed human CYP 3A4 was with AXDD14, which was extensively activated. Interestingly, metabolism of dapsone was low using the expressed CYP 3A4. In the two-compartment system using human liver microsomes, AXDD14, K-130 and ABDD5 were oxidized to a significantly lesser extent compared with dapsone and these preliminary findings indicate that future development of these compounds may be worthwhile.
使用三种代谢系统（大鼠、异源表达的CYP3A4和人肝脏）在体外评估了12种氨苯砜（4,4'-二氨基二苯砜）类似物。分别以人红细胞和中性粒细胞作为靶细胞，在双室模型中研究高铁血红蛋白的形成，在单室模型中研究细胞毒性。在以大鼠微粒体作为生成系统、高铁血红蛋白作为终点的双室系统中，测试的生成高铁血红蛋白能力最弱的是2-甲基-4-丙基氨基（AXDD14）、2-羟基-4-4'氨基（ABDD5）衍生物和一种砜/甲氧苄啶衍生物（K-130）。氨苯砜本身、2-甲氧基-4-乙氨基（W10）和2-羟基-4-乙氨基化合物（ABDD39）毒性最大。在使用大鼠微粒体的单室细胞毒性试验中，AXDD14再次属于毒性最小的，2-甲基-4-环戊基衍生物（AXDD17）以及出人意料的ABDD39也是如此。细胞毒性最大的化合物再次包括氨苯砜本身以及两种2-三氟甲基衍生物。异源表达的人CYP 3A4显示出的唯一显著高铁血红蛋白形成和细胞毒性与AXDD14有关，AXDD14被广泛激活。有趣的是，使用表达的CYP 3A4时氨苯砜的代谢很低。在使用人肝脏微粒体的双室系统中，与氨苯砜相比，AXDD14、K-130和ABDD5的氧化程度明显较低，这些初步发现表明这些化合物未来可能值得进一步开发。
