Ono Chiho, Tanaka Makoto
Drug Metabolism and Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co., Ltd, 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan.
J Pharm Pharmacol. 2003 Aug;55(8):1127-33. doi: 10.1211/002235703322277168.
To define the binding characteristics of fluoroquinolones to synthetic levodopa melanin, the binding of various drugs, including levofloxacin and ofloxacin, and positive controls (timolol and chloroquine), was investigated in-vitro. The affinity and capacity of the drug binding were calculated by Langmuir's adsorption isotherm. The affinity constant (K) and the binding capacity (r(max)) of levofloxacin were similar to those of timolol and much lower than those of chloroquine. Racemic ofloxacin and its enantiomers showed similar K and r(max), suggesting that the binding lacked stereoselectivity. The binding experiment with levofloxacin derivatives indicated that the basic nitrogen atom at position 7 of the quinolone ring, but not carboxyl group at position 3, would play a critical role in the interaction of fluoroquinolones with melanin. The melanin-drug complexes of levofloxacin and chloroquine were washed with neutral phosphate buffer, ethanol and 1 M HCl solution to explain the nature of the interaction of melanin with the drugs. Electrostatic forces mainly participate in the formation of the chloroquine-melanin complex, whereas van der Waals' and hydrophobic interactions are involved in the levofloxacin-melanin complex in addition to electrostatic forces. The interactions of various fluoroquinolones such as norfloxacin, enoxacin, sparfloxacin, ciprofloxacin and lomefloxacin with melanin were also studied. The results showed that the relative K value was: chloroquine approximately ciprofloxacin, sparfloxacin >/= lomefloxacin > timolol, levofloxacin approximately enoxacin, norfloxacin, and that the relative r(max) value was: norfloxacin, enoxacin >/= chloroquine, sparfloxacin > levofloxacin, ciprofloxacin, timolol, lomefloxacin. The fluoroquinolones vary in their affinity and capacity to bind with melanin, and ciprofloxacin and sparfloxacin showed a stronger interaction with melanin than the other fluoroquinolones studied.
为了确定氟喹诺酮类药物与合成左旋多巴黑色素的结合特性，对包括左氧氟沙星和氧氟沙星在内的多种药物以及阳性对照（噻吗洛尔和氯喹）的体外结合情况进行了研究。通过朗缪尔吸附等温线计算药物结合的亲和力和容量。左氧氟沙星的亲和常数（K）和结合容量（r(max)）与噻吗洛尔相似，远低于氯喹。消旋氧氟沙星及其对映体显示出相似的K和r(max)，表明结合缺乏立体选择性。左氧氟沙星衍生物的结合实验表明，喹诺酮环7位的碱性氮原子而非3位的羧基在氟喹诺酮类药物与黑色素的相互作用中起关键作用。用中性磷酸盐缓冲液、乙醇和1 M盐酸溶液洗涤左氧氟沙星和氯喹的黑色素 - 药物复合物，以解释黑色素与药物相互作用的性质。静电力主要参与氯喹 - 黑色素复合物的形成，而除静电力外，范德华力和疏水相互作用也参与左氧氟沙星 - 黑色素复合物的形成。还研究了诺氟沙星、依诺沙星、司帕沙星、环丙沙星和洛美沙星等多种氟喹诺酮类药物与黑色素的相互作用。结果表明，相对K值为：氯喹≈环丙沙星，司帕沙星≥洛美沙星＞噻吗洛尔，左氧氟沙星≈依诺沙星、诺氟沙星；相对r(max)值为：诺氟沙星、依诺沙星≥氯喹、司帕沙星＞左氧氟沙星、环丙沙星、噻吗洛尔、洛美沙星。氟喹诺酮类药物与黑色素结合的亲和力和容量各不相同，环丙沙星和司帕沙星与黑色素的相互作用比所研究的其他氟喹诺酮类药物更强。
