Li Qigui, Kozar Michael P, Shearer Todd W, Xie Lisa H, Lin Ai J, Smith Kirsten S, Si Yuanzheng, Anova Lalaine, Zhang Jing, Milhous Wilbur K, Skillman Donald R
Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20307-5100, USA.
Antimicrob Agents Chemother. 2007 Aug;51(8):2898-904. doi: 10.1128/AAC.00932-06. Epub 2007 Jun 11.
Pyrroloquinazolinediamine (PQD) derivatives such as tetra-acetamide PQD (PQD-A4) and bis-ethylcarbamyl PQD (PQD-BE) were much safer (with therapeutic indices of 80 and 32, respectively) than their parent compound, PQD (therapeutic index, 10). Further evaluation of PQD-A4 and PQD-BE in single and multiple pharmacokinetic (PK) studies as well as corresponding toxicity studies was conducted with rats. PQD-A4 could be converted to two intermediate metabolites (monoacetamide PQD and bisacetamide PQD) first and then to the final metabolite, PQD, while PQD-BE was directly hydrolyzed to PQD without precursor and intermediate metabolites. Maximum tolerant doses showed that PQD-A4 and PQD-BE have only 1/12 and 1/6, respectively, of the toxicity of PQD after a single oral dose. Compared to the area under the concentration-time curve for PQD alone (2,965 ng.h/ml), values measured in animals treated with PQD-A4 and PQD-BE were one-third (1,047 ng.h/ml) and one-half (1,381 ng.h/ml) as high, respectively, after an equimolar dosage, suggesting that PQD was the only agent to induce the toxicity. Similar results were also shown in multiple treatments; PQD-A4 and PQD-BE generated two-fifths and three-fifths, respectively, of PQD concentrations, with 8.8-fold and 3.8-fold safety margins, respectively, over the parent drug. PK data indicated that the bioavailability of oral PQD-A4 was greatly limited at high dose levels, that PQD-A4 was slowly converted to PQD via a sequential three-step process of conversion, and that PQD-A4 was significantly less toxic than the one-step hydrolysis drug, PQD-BE. It was concluded that the slow and smaller release of PQD was the main reason for the reduction in toxicity and that the active intermediate metabolites can still maintain antimalarial potency. Therefore, the candidate with multiple-step hydrolysis of PQD could be developed as a safer potential agent for malaria treatment.
吡咯并喹唑啉二胺（PQD）衍生物，如四乙酰酰胺PQD（PQD - A4）和双乙基氨基甲酰基PQD（PQD - BE），比它们的母体化合物PQD（治疗指数为10）安全得多（治疗指数分别为80和32）。在大鼠中对PQD - A4和PQD - BE进行了单次和多次药代动力学（PK）研究以及相应的毒性研究。PQD - A4首先可转化为两种中间代谢产物（单乙酰酰胺PQD和双乙酰酰胺PQD），然后再转化为最终代谢产物PQD，而PQD - BE则直接水解为PQD，无前体和中间代谢产物。最大耐受剂量表明，单次口服给药后，PQD - A4和PQD - BE的毒性分别仅为PQD的1/12和1/6。与单独使用PQD时的浓度 - 时间曲线下面积（2965 ng·h/ml）相比，在等摩尔剂量后，用PQD - A4和PQD - BE处理的动物中测得的值分别为其三分之一（1047 ng·h/ml）和二分之一（1381 ng·h/ml），这表明PQD是唯一诱导毒性的药物。多次给药时也显示出类似结果；PQD - A4和PQD - BE分别产生了PQD浓度的五分之二和五分之三，相对于母体药物的安全边际分别为8.8倍和3.8倍。药代动力学数据表明，高剂量水平下口服PQD - A4的生物利用度受到极大限制，PQD - A4通过连续三步转化过程缓慢转化为PQD，并且PQD - A4的毒性明显低于一步水解药物PQD - BE。得出的结论是，PQD释放缓慢且量少是毒性降低的主要原因，并且活性中间代谢产物仍可保持抗疟效力。因此，具有PQD多步水解的候选药物可开发为更安全的潜在抗疟药物。
