Shin Ho-Chul, Kim Jong-Choon, Chung Moon-Koo, Jung Yong-Ho, Kim Jin-Suk, Lee Mi-Kyung, Amidon Gordon L
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Comp Biochem Physiol C Toxicol Pharmacol. 2003 Sep;136(1):95-102. doi: 10.1016/j.cca.2003.08.004.
We investigated maternal and fetal tissue distribution of DW-116, a newly developed fluoroquinolone with a broad antibacterial spectrum against both G(+) and G(-) bacteria, in pregnant rats. After oral administration of [14C]-DW-116 (labeled 1 mg and unlabeled 500 mg/kg) to female rats on the 18th day of gestational, groups of three rats were killed at various time points up to 24 h, and plasma and tissues were collected, processed and analyzed. [14C]-DW-116 was rapidly absorbed, and distributed into the maternal and fetal tissues, and it declined in a biphasic manner with elimination half-lives (t(1/2)) of 10-15 h and mean residence times (MRT(0-24 h)) of 4-9 h. The radioactivity in most tissues of both dams and fetus reached its peak within 1 h and radioactivity levels of up to 10-25% of the peak level were maintained until 24 h after dosing. Among various tissues, the radioactivity in the maternal lungs was the highest (27 times that of plasma) at the C(max). Radioactivity in other tissues including liver, kidney, heart, lung, brain, spleen, mammary gland, placenta, ovary and uterus was higher than that in the maternal plasma (one- to three-fold). The tissue-to-plasma partition coefficient (K(p), AUC(0-24 h,tissue)/AUC(0-24 h,plasma)) of [14C]-DW-116 in maternal tissues was highest in the lung (K(p)=3.7), followed by the spleen (2.2), kidney (2.0), liver (1.8), heart (1.5), placenta (1.3), brain (1.3), ovary (1.1), uterus (1.1), and mammary gland (1.0). The tissue-to-plasma partition coefficient values in fetal tissues were heart (K(p)=2.2), kidney (2.1), liver (1.9), lung (1.6) and brain (1.4). When lactating rats were given a single oral dose of [14C]-DW-116, the radioactivity was rapidly secreted into the milk with K(p) of 1.7 at T(max) (0.5 h). These results indicate that DW-116 or its related metabolite(s) rapidly cross the blood-placenta and blood-milk barrier, extensively distribute into the fetal tissues, and are eliminated from the body in a prolonged manner. This study sheds insights into the maternal and fetal tissue distribution of DW-116 and will be useful for assessing both therapeutic and toxicological relevance of DW-116 in pregnant subjects.
我们研究了新型氟喹诺酮类药物DW - 116在妊娠大鼠体内的母体和胎儿组织分布情况。DW - 116具有广谱抗菌活性，对革兰氏阳性菌和革兰氏阴性菌均有抗菌作用。在妊娠第18天给雌性大鼠口服[14C] - DW - 116（标记剂量1 mg，未标记剂量500 mg/kg），在给药后24小时内的不同时间点处死每组3只大鼠，收集血浆和组织，进行处理和分析。[14C] - DW - 116吸收迅速，分布于母体和胎儿组织中，其消除呈双相性，消除半衰期（t(1/2)）为10 - 15小时，平均驻留时间（MRT(0 - 24 h)）为4 - 9小时。母体和胎儿大多数组织中的放射性在1小时内达到峰值，给药后24小时内放射性水平维持在峰值水平的10% - 25%。在各个组织中，母体肺组织中的放射性在C(max)时最高（是血浆的27倍）。包括肝脏、肾脏、心脏、肺、脑、脾脏、乳腺、胎盘、卵巢和子宫在内的其他组织中的放射性高于母体血浆（1至3倍）。[14C] - DW - 116在母体组织中的组织 - 血浆分配系数（K(p)，AUC(0 - 24 h,tissue)/AUC(0 - 24 h,plasma)）在肺中最高（K(p)=3.7），其次是脾脏（2.2）、肾脏（2.0）、肝脏（1.8）、心脏（1.5）、胎盘（1.3）、脑（1.3）、卵巢（1.1）、子宫（1.1）和乳腺（1.0）。胎儿组织中的组织 - 血浆分配系数值依次为心脏（K(p)=2.2）、肾脏（2.1）、肝脏（1.9）、肺（1.6）和脑（1.4）。给哺乳期大鼠单次口服[14C] - DW - 116时，放射性迅速分泌到乳汁中，在T(max)（0.5小时）时K(p)为1.7。这些结果表明，DW - 116或其相关代谢物迅速穿过血 - 胎盘和血 - 乳屏障，广泛分布于胎儿组织中，并在体内长时间消除。本研究深入了解了DW - 116在母体和胎儿组织中的分布情况，将有助于评估DW - 116在妊娠受试者中的治疗和毒理学相关性。
