Mizuki Y, Fujiwara I, Yamaguchi T
Department of Pharmacokinetics, Dainippon Pharmaceutical Co., Ltd, Osaka, Japan.
J Antimicrob Chemother. 1996 May;37 Suppl A:41-55. doi: 10.1093/jac/37.suppl_a.41.
Fluoroquinolone derivatives interact with methylxanthines (theophylline, caffeine) and metallic ion-containing drugs to different degrees. The rat appears to be a suitable model for predicting such interactions in man. It has been possible to determine the relationship between the chemical structure of the fluoroquinolone and the magnitude of the interaction. Fluoroquinolones with a bulky substituent at the position 8, such as sparfloxacin, lomefloxacin and fieroxacin, are less prone to interact with theophylline than those without an 8-substituent, such as enoxacin. This substituent determines the planarity of the whole fluoroquinolone molecule and the interaction tends to be more significant for planar fluoroquinolones. Furthermore, a 4'-nitrogen atom in the 7-piperazinyl group is essential for the interaction to occur. The nitrogen atom is possibly the site that binds cytochrome P-450, which catalyses theophylline metabolism. The reduction in bioavailability of fluoroquinolones by concurrent administration of aluminium hydroxide is more striking for derivatives with fewer substituents on the essential structure and on the piperazinyl group, such as norfloxacin, ciprofloxacin and enoxacin. Substitution at the 5-position diminishes the interaction, which suggests that the 5-substituent may affect the formation and/or stability of unabsorbable chelate complex which is the probable cause of the interaction. These findings are potentially useful in designing fluoroquinolones less prone to drug interactions.
氟喹诺酮衍生物与甲基黄嘌呤（茶碱、咖啡因）以及含金属离子的药物存在不同程度的相互作用。大鼠似乎是预测人体此类相互作用的合适模型。已能够确定氟喹诺酮的化学结构与相互作用强度之间的关系。在8位带有庞大取代基的氟喹诺酮，如司帕沙星、洛美沙星和氟罗沙星，与茶碱相互作用的可能性低于那些没有8位取代基的氟喹诺酮，如依诺沙星。该取代基决定了整个氟喹诺酮分子的平面性，对于平面型氟喹诺酮，相互作用往往更为显著。此外，7 - 哌嗪基中的4'-氮原子对于相互作用的发生至关重要。该氮原子可能是与催化茶碱代谢的细胞色素P - 450结合的位点。同时给予氢氧化铝时，对于在基本结构和哌嗪基上取代基较少的衍生物，如诺氟沙星、环丙沙星和依诺沙星，氟喹诺酮生物利用度的降低更为显著。在5位进行取代可减少相互作用，这表明5位取代基可能会影响不可吸收螯合物的形成和/或稳定性，而这种螯合物可能是相互作用的原因。这些发现对于设计不易发生药物相互作用的氟喹诺酮可能具有潜在用途。
