Placental Transfer and Pharmacokinetics of a Single Oral Dose of the Fluoroquinolone Antibacterial DW-116 in Rats

랫드에서 fluoroquinolone 항균제 DW-116의 단회 경구투여에 의한 태반통과와 약물동태연구

  • 김종춘 (한국화학연구원 안전성연구센터) ;
  • 신호철 (한국화학연구원 안전성연구센터) ;
  • 허정두 (한국화학연구원 안전성연구센터) ;
  • 이종화 (한국화학연구원 안전성연구센터) ;
  • 정문구 (한국화학연구원 안전성연구센터) ;
  • 윤효인 (충남대학교 수의과대학 수의학과)
  • Published : 2002.03.01


The present study was conducted to investigate the placental transfer and pharmacokinetics of the flu-oroquinolone antibacterial DW-116 in pregnant rats. The placental transfer and pharmacokinetics of DW-116 were examined after a single oral dose of 500 mg $^{14}C$ DW-116/kg on gestational day 18. Maternal and fetal tissues were collected at 0.17 0.5,1,2,4,8, and 24 h after dosing. Maximum radioactivity was detected in maternal plasma, placenta, and whole fetus at 1 h, and in amniotic plasma at 4 h after dosing. Thereafter, radioactivity gradually disappeared from these tissues and was 16~28% of maximum levels at 24 h after dosing. Radioactivity in whole fetus were higher than those in the maternal plasma and placenta. The $T_{1/2,abs}$, $T_{1/2,{\beta}},$ AUC, $T_{max},$ and $C_{max}$ in the maternal plasma were approximately 6 min, 13.3 h, 1620 $ug^*hr/ml,$ 0.5 h, and 136 ug/ml, respectively. Those in the placenta were approximately 20 min, 12.3 h, 2150 $ug^*h/$m\ell$,$ 1.0 h, and 172 ug/ml, respectively. Those in the whole fetus were 13 min, 12.8 h,2549 $ug^*h/$m\ell$,$ 1 h, and 191 ug/ml, respectively. In the amniotic fluid of maternal uterus, the 4T_1/2,abs}$, $T1/2,{\beta},$ AUC, $T_{max},$ and $C_{max}$ were approximately 1.3 h,9.3 h,2508 $ug^*h/$m\ell$,$ 4.4 h, and 135 ug/ml, respectively. While DW-116 disappeared biphasically from maternal plasma, whole fetus and placenta, it was eliminated monophasically from amniotic fluid. In conclusion, this study demonstrated that the absorption and distribution of DW-116 in maternal plasma and placenta were extensively rapid, and that the test chemical well passed the blood-placenta barrier and was transferred to the fetus.



  1. Abu-Qare, A. W., Brownie, C. F. and Abou-Donia, M. B (2000). Placental transfer and pharmacokinetics of a single dose of [$^{14}C$]P-nitropheno1 in rats, Arch. Toxicol., 74, 388-396
  2. Choi, K. H., Hong, J. S., Kim, S. K., Yoon, S. J, and Choi, E C. (1997). In-vitro and in-vivo aclivities of DW-116, a new fluoroquinolone. J. Antimicrob. Chemother., 39, 509-514
  3. Chung, M. K., Kim, J. C. and Lim, K. H. (1999). Deve10p-mental toxicity of DW-116, a new fluoroquinolone antibac-terial agenl, in rats. .J. Toxicol. Pub. Heatth, 15, 495-501
  4. Chung, M. K., Kim, J. C. and Roh, J. K. (1998). Embryotoxic effects of SKI 2053R, a new potential anticancer agent, in rats. Reprod. Toxicol., 12, 375-381
  5. Cufffini, A. M., Tullio, V., Allocco, A., Paizis, G., De Leo, C. and Carlone, N. A. (1994). Effect of rufloxacin upon non specific immune defences: in-vitro, ex-vivo and in-vivo results..J. Antimicrob. Chemother., 34, 545-553
  6. Ebisuno, S., Inagaki, T., Kohjimoto, Y. and Ohkawa, T. (1997). The cytotoxic effects of fleroxacin and cipro-floxacin on transitional cell carcinoma in vitro. Cancer, 80, 2263-2267<2263::AID-CNCR7>3.0.CO;2-V
  7. Gibaldi, M. (1991). Biopharmaceutcs and Clinical Pharma-cokinetics (4th ed), pp. 5, Lea and Febiger, Philadelphia
  8. Gootz, T. D. and Brighly, K. E. (1998). Chemistry and mechanism of action of the quinolone antibacterials. In The Quinotones (2nd ed) (V.T. Andriole, Ed.), pp. 29-80, Academic Press, San Diego
  9. Han, K. O., Hwang, Y. H., Lee, W. Y., Chung, Y. H., Yoon, S. J. and Lee, D. K. (1995). In vitro and in vivo activity of DW-116, a new quinolone antibiotic. 35th Intersci. Conf. Antimicrob. Aqents Chemother. F193 (Abslact)
  10. Hwang, Y. H., Han, K. 0., Lee, J., Yang, H. B., Chung, Y. H., Yoon, S. J. and Lee, D. K. (1997). In vitro and in vivo antibacterial activity of DW-116, a new quinolone antibio-tic. J. Appl. Pharmacol., 5, 187-193
  11. Hooper, D. C. and Wolfson, J. S. (1991). Fluoroqumolone antibactehal agents. New Engl. J. Med., 324, 384-394
  12. Kato, R., Case, D. E., Hakusui, H., Noda, K., Sagami, F., Horii, I., Mayahara, H., Cayen, M. N., Marriott, T. B. and Igarashi, T. (1993). Toxicokinetics: its significance and practical problems. J. Toxicol. ScL, 18, 211-238
  13. Kim, J. C., Yun, H. I., Shin, H. C., Han, S. S. and Chung, M. K. (2000). Embryo lethality and teratogenicity of a new fluoroquinolone antibactenal DW-116 in rats. Arch. Toxi-C.0l.,74, 120-124
  14. Kim, J. C., Shin, H. C., Cha, S. W., Koh, W. S., Chung, M. K. and Han, S. S. (2001). Evaluation of developmental toxicity in rats exposed to the environmental estrogen bisphenol A during pregnancy. Life Sci., 69, 2611-2625
  15. Koga, H., Itoh, A., Murayama, S., Suzue, S. and Ihkura, T.(1980). Structure-activity relationships of antibactehal 6,7-aiid 7,8-disubstituted 1-a1ky1-1,4-dihydro-4-oxoqumo1ine-3-carboxylic acids. J. Med. Chem., 23, 1358-1363
  16. Lee, D. K. (1995). Pharmacokinetic study of a new quinolone, DW-116. Drugs, 49, 323-325
  17. Lesher, G. Y., Forelich, E. D., Gruet, M. D., Bailey, J. H. and Brundage, R. P. (1962). 1,8-Naphthyridine derivalives. A new class of chemotherapeutic agents. J. Med. Pharm. Chem., 5, 1063-1068
  18. Morinaga, T., Fujii, S., Furukawa, S., Kikumori, M., Yasuhira, K., Shindo, Y., Watanabe, M. and Sumi, N. (1996). Reproductive and developmental toxicity studies of Pruli-floxacin (NM441) (3): a teratogenicity study in rabbits by oral administration. J. ToxicoI. Sci., 21(Suppl. I), 207-217
  19. Neu, H. C. (1992). Quinolone antimicrobial agents. Annu. Rev. Med., 43, 465-486
  20. Park, Y. H., Jung, B. H., Chung, B. C., Park, J, and Mitoma, C. (1997). Metabolic disposition of the new fluoro-quinolone antibacterial agent DW116 in rats. Drug. Metabot. Disposit., 25, 1101-1103
  21. Saillenfait, A. M., Payan, J. ., Langonne, I., Gallissot, F., Sabate, J. P., Beydon, D. and Fabry, J. P. (1999).Assessment of the developmental toxicity and placental transfer of 1,2-diethy1benzene in rats. Food Chem. ToxicoI., 37, 1089-1096
  22. Schwartz, S. (2001). Providing toxicokinetics support for reproductive toxicology studies in pharmaceutical deve1op-ment. Arch. Toxicol., 75, 381-387
  23. Shimada, J. and Hori, S. (1992). Adverse effects of fluoroqui-nolones. Prog, Drug. Res., 38, 133-143
  24. Shin, H. C., Kim, E. J. and Han, S. S. (2000). Overview of toxicokinetics. Korean J. Lab. Ani. Sci., 16, 115-122
  25. Stahlmann, R. and Lode, H. (1999). Toxicity of quinulones. Drugs 58(Supp1. 2), 37-42
  26. Suzuki, T., Ishikawa, S., Ogawa, Y., Takahashi, T. and Abe, Y. (1990). Teratological study of fleroxacin in rabbits. Chemotheraphy, 38(S-2), 272-279
  27. Takayama, S., Hirohashi, M., Kato, M. and Shimada, H. (1995). Toxicity of quinolone antimicrobial agents. J. Toxicol. Environ. Health, 45, 1-45
  28. Takayama, S., Watanabe, T., Akiyama, Y, Ohura, K., Harada, S., Matsuhashi, K., Mochida, K. and Yamashita, N. (1986). Reproductive toxicity of ofloxacin. Arzneim. Forsch., 36, 1244-1248
  29. Umemura, T., Sasa, H., Lizuka, T. and Yanagila, T. (1988). Teratological study of oral administration of NY-198 in rabbits. Chemotheraphy, 36(S-2), 391-410
  30. Walker, R. C. (1999). The fluoroquinolons. Mayo Clin. Proc., 74, 1030-1037
  31. Watanabe, T., Fujikawa, K., Harada, S., Ohura, K., Sasaki, T. and Takayama, S. (1992). Reproductive loxicity of the new quinolone antibacterial agent levofloxacin in rats and rabbils. Arzneim. Forsch., 42, 374-377
  32. Wolfson, J.S. and Hooper, D. C. (1991). Overview of fluoro-quinolone safety. Am. J. Med., 91, 153S-161S
  33. Yamashita, Y, Ashizawa, T., Morimoto, M., Hosomi, J. and Nakano, H. (1992). Antitumor quinolone with mammalian topoisomerase II mediated DNA cleavage activily. Cancer Res., 52, 2818-2822
  34. Yoon, S. J., Chun, Y. H., Lee, C. W., Oh, Y. S., Choi, D. R. and Kim, N. D. (1996) Novel quinolone carboxylic acid derivatives. USA Patent No. 5496947-A-6
  35. Yu, I. L., Chung, S. J., Lee, M. H. and Shim, C. K. (1997) Pharmacokinetics of 1-(5-f1uoro-2pyridy1)-6-f1uoro-7-(4-methy1-1-piperaziny1)-1,4-dihydio-4-oxoquino1one-3-carboxylic acid hydrochloride (DW-116), a new quinolone antibiotic in rats. J. Pharmacol. Sci., 86, 550-553