Maffei Facino R, Carini M, Tofanetti O
Istituto Chimica Farmaceutica Tossicologica, Milan, Italy.
Pharmacol Res Commun. 1988 Apr;20(4):265-76. doi: 10.1016/s0031-6989(88)80064-x.
Chronic exposure of rats to the hypolipidemic agent tiadenol causes a dramatic dose-dependent increase of peroxisomal beta-oxidation activity. To elucidate which metabolite of the drug is the "proximate" inducer (tiadenol is eliminated completely in metabolized form after acute administration) we investigated the qualitative and quantitative metabolic profile of the drug at different doses (50, 150, 300 mg/Kg in two-weeks chronically treated rats, in parallel to that of a model compound, tiadenol-disulfoxide, a weak inducer of palmitoyl-CoA oxidation activity. No changes in the biodisposition of tiadenol (and tiadenol-disulfoxide) were found following chronic treatment for all the doses tested. For both the compounds a strict correlation was evidenced between the extent of formation of carboxylic metabolites and their inductive potencies on peroxisomal beta-oxidation activity. This indicates that tiadenol carboxylic metabolites act as the enzymatic effectors.
大鼠长期接触降血脂药物替阿地诺会导致过氧化物酶体β-氧化活性呈显著的剂量依赖性增加。为阐明该药物的哪种代谢产物是“直接”诱导剂（替阿地诺在急性给药后以代谢形式完全消除），我们研究了不同剂量（50、150、300mg/Kg，对两周慢性治疗的大鼠）下该药物的定性和定量代谢谱，同时研究了模型化合物替阿地诺二亚砜（棕榈酰辅酶A氧化活性的弱诱导剂）的代谢谱。在所有测试剂量的慢性治疗后，未发现替阿地诺（和替阿地诺二亚砜）的生物处置有变化。对于这两种化合物，羧酸代谢产物的形成程度与其对过氧化物酶体β-氧化活性的诱导能力之间存在严格的相关性。这表明替阿地诺羧酸代谢产物充当酶效应物。
