Tyson C A, LeValley S E, Chan R, Hobbs P D, Dawson M I
J Pharmacol Exp Ther. 1984 Mar;228(3):676-81.
The potential efficacy of drug combinations that employ an ionophore to mobilize excess hepatic Fe and transport it to the gut for chelation to nonabsorbable polymers and excretion was evaluated in three ways: 1) two-phase partition experiments to assess the ionophoretic capability of lipid-soluble Fe(III)-chelators; 2) in vitro screening with Fe-loaded hepatocyte cultures; and 3) evaluation in Fe-dextran-loaded mice given a low-Fe-containing diet for maximal sensitivity. In the partition experiments, desferal (DF), (desferri)ferrichrome, pyridoxyl isonicotinoyl acid hydrazone hydrochloride (PINH), 2,3-dihydroxybenzoic acid, cholylhydroxamic acid and caffeic acid were effective to varying degrees in transferring Fe(III) from an aqueous to an organic hydrophobic phase. PINH, the most effective, combined with poly[vinylamine-vinyl(2,3-dihydroxybenzenecarboxamide)-vinyl sulfonate sodium salt] (DHBP), increased net 59Fe release from Fe-loaded hepatocytes above the sum of that released by each drug alone and comparable with DF-induced levels. In the mouse bioassay, the combination of PINH (8.1 mg/kg) and DHBP (170 mg/kg 2 times daily) caused a 32% increase in fecal Fe output, comparable with total Fe excretion with DF, but higher doses were toxic and lower doses ineffective. Furthermore, less than 5% of the total Fe load administered was excreted during the 4-day treatment period by either DF or the PINH-DHBP drug combination.
采用离子载体动员肝脏中过量铁并将其转运至肠道，使其与不可吸收聚合物螯合并排泄的药物组合的潜在疗效通过以下三种方式进行评估：1）两相间分配实验，以评估脂溶性铁（III）螯合剂的离子载体能力；2）用铁负载的肝细胞培养物进行体外筛选；3）在给予低铁饮食以获得最大敏感性的葡聚糖铁负载小鼠中进行评估。在分配实验中，去铁胺（DF）、（去铁）高铁菌素、盐酸吡啶异烟酰腙（PINH）、2,3 - 二羟基苯甲酸、胆酰氧肟酸和咖啡酸在将铁（III）从水相转移至有机疏水相方面均有不同程度的效果。最有效的PINH与聚[乙烯胺 - 乙烯基（2,3 - 二羟基苯甲酰胺） - 乙烯磺酸钠盐]（DHBP）联合使用时，从铁负载肝细胞释放的净59Fe量高于每种药物单独释放量之和，且与DF诱导的水平相当。在小鼠生物测定中，PINH（8.1 mg/kg）和DHBP（170 mg/kg，每日2次）的组合使粪便铁排出量增加了32%，与DF的总铁排泄量相当，但高剂量有毒，低剂量无效。此外，在为期4天的治疗期间，DF或PINH - DHBP药物组合排出的铁总量不到给药总铁量的5%。
