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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1995 Jan;86(1):111–116. doi: 10.1111/j.1349-7006.1995.tb02995.x

Pharmacological Correlation between Total Drug Concentration and Lactones of CPT‐11 and SN‐38 in Patients Treated with CPT‐11

Yasutsuna Sasaki 1,✉, Yasushi Yoshida 2, Kenichi Sudoh 2, Hideo Hakusui 2, Hirofumi Fujii 1, Tomoko Ohtsu 1, Hisashi Wakita 1, Tadahiko Igarashi 1, Kuniaki Itoh 1
PMCID: PMC5920577  PMID: 7737902

Abstract

The pharmacokinetics of 7‐ethyl‐10‐[4‐(1‐piperidino)‐1‐piperidino]carbonyloxycamptothecin (CPT‐11) and its active metabolite, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), were examined to establish the pharmacokinetic variability of the active lactones of CPT‐11 and SN‐38 in comparison with that of the total (lactone and carboxylates) plasma CPT‐11 and SN‐38. Twelve patients with malignancies were entered in the study. All received 100 mg/m2 of CPT‐11 by intravenous drip infusion over 90 min. Blood was sampled at 10 time points in heparin‐containing syringes. Analysis by high‐performance liquid chromatography showed that the ratio of CPT‐11 lactone to total CPT‐11 concentration was highest (66%) just after the end of infusion and gradually decreased to 30% at 24 h. Almost 70% of SN‐38 lactone was detected after the end of infusion and this decreased to 50% within 24 h. The standard errors of percent lactone of CPT‐11 or SN‐38 to total drug concentration at each sampling point were less than 12%. The area under the concentration‐time curve (AUC) of total CPT‐11 and that of total SN‐38 were significantly correlated with the AUCs of the lactone CPT‐11 and those of lactone SN‐38, respectively. We conclude that, for practical purposes, monitoring of total CPT‐11 and SN‐38 has essentially the same clinical significance as monitoring of lactone CPT‐11 and SN‐38.

Keywords: CPT‐11, SN‐38, Lactone, Pharmacokinetics

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REFERENCES

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REFERENCES

  • 1. ) Wall , M. E. , Wani , M. C. , Cook , C. E. , Palmar , K. H. , MacPhail , A. T. and Simm , G. A.Plant antitumor agents. 1. The isolation and structure of camptothecin, a novel alkaloid leukemia and tumor inhibition from Camptotheca accuminata . J. Am. Chem. Soc. , 88 , 3888 – 3890 ( 1966 ). [Google Scholar]
  • 2. ) Gottilieb , J. A. , Guarino , A. M. , Call , J. B. , Oliverio , V. T. and Block , J. B.Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC‐100880) . Cancer Chemother. Rep. , 54 , 461 – 470 ( 1970 ). [PubMed] [Google Scholar]
  • 3. ) Muggia , F. M. , Creeaven , P. J. , Hansen , H. H. and Selawry , O. S.Phase I clinical trial of weekly and daily treatment with camptothecin (NSC‐100880): correlation with preclinical studies . Cancer Chemother. Rep. , 56 , 515 – 521 ( 1972 ). [PubMed] [Google Scholar]
  • 4. ) Miyasaka , T. , Sawada , S. , Nokata , K. , Sugino , E. and Mutai , M.New camptothecin derivative. Japanese Patent Kokai 201 – 207 ( 1987 ) ( in Japanese ).
  • 5. ) Kunimoto , T. , Nitta , K. , Tanaka , T. , Uehara , N. , Baba , H. , Takeuchi , M. , Yokokura , T. , Sawada , S. , Miyasaka , T. and Mutai , M.Antitumor activity of 7‐ethyl‐10‐[4‐(1‐piperidino)‐1‐piperidino]carbonyloxycamptothecin, a novel water‐soluble derivative of camptothecin, against murine tumors . Cancer Res. , 47 , 5944 – 5947 ( 1987 ). [PubMed] [Google Scholar]
  • 6. ) Tsuruo , T. , Matsuzaki , T. , Matsushita , T. , Saito , H. and Yokokura , T.Antitumor effect of CPT‐11, a new derivative of camptothecin, against pleiotropic drug‐resistant tumors in vitro and in vivo . Cancer Chemother. Pharmacol. , 21 , 71 – 74 ( 1988 ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Kaneda , M. , Nagata , H. , Furuta , T. and Yokokura , T.Metabolism and pharmacokinetics of the camptothecin analogue CPT‐11 in the mouse . Cancer Res. , 50 , 1715 – 1720 ( 1990 ). [PubMed] [Google Scholar]
  • 8. ) Tsuji , T. , Kaneda , N. , Kado , K. , Yokokura , T. , Yoshimoto , T. and Tsuru , D.CPT‐11 converting enzyme from rat serum: purification and some properties . J. Pharmacobio-Dyn. , 14 , 341 – 349 ( 1991 ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Slichenmyer , W. J. , Rowinsky , E. K. , Donehower , R. C. and Kaufmann , S. H.The current status of camptothecin analogues as antitumor agents . J. Natl. Cancer Inst. , 85 , 271 – 291 ( 1993 ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Negoro , S. , Fukuoka , M. , Masuda , N. , Takada , M. , Kusunoki , Y. , Matsui , K. , Takifuji , N. , Kudoh , S. , Niitani , H. and Taguchi , T.Phase I study of weekly intravenous infusion of CPT‐11, a new derivative of camptothecin, in the treatment of advanced non‐small‐cell lung cancer . J. Natl. Cancer Inst. , 83 , 1164 – 1168 ( 1991 ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Ohe , Y. , Sasaki , Y. , Shinkai , T. , Eguchi , K. , Tamura , T. , Kojima , A. , Kunikane , H. , Okamoto , H. , Karato , A. , Ohmatsu , H. and Kanjawa , F.Phase I study and pharmacokinetics of CPT‐11 with 5‐day continuous infusion . J. Natl. Cancer Inst. , 84 , 972 – 974 ( 1992 ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Sasaki , Y. , Hakusui , H. , Mizuno , S. , Morita , M. , Miya , T. , Eguchi , K. , Shinkai , T. , Tamura , T. , Ohe , Y. and Saijo , N.A pharmacokinetic and pharmacodynamic analysis of CPT‐11 and its active metabolite SN‐38 . Jpn. J. Cancer Res. , 86 , 101 – 110 ( 1995 ). [DOI] [PMC free article] [PubMed] [Google Scholar]
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  • 14. ) Stabus , A. E. , Rutherford , M. , Snuffer , P. and Feller , D.Kinetics of ring opening of camptothecin analogues and topotecan in plasma and whole blood . Proc. Am. Assoc. Cancer Res. , 33 , 531 ( 1992 ). [Google Scholar]
  • 15. ) Declaration of Helsinki : recommendation guiding medical doctors in biomedical research involving human subjects . World Medical Association, Helsinki ( 1964 ).
  • 16. ) Yoshida , Y. , Hashimoto , K. , Yoshida , N. , Sudoh , K. and Hakusui , H.Pharmacokinetics of closed lactone and open‐ring CPT‐11 in dog . Xenobiot. Metab. Dispos. , 8 , 854 , ( 1993 ) ( in Japanese ). [Google Scholar]
  • 17. ) Grochow , L. B. , Rowinsky , E. K. , Johnson , R. , Ludeman , S. , Kaufmann , S. H. , McCabe , F. L. , Smith , B. R. , Hurowittz , L. , DeLisa , A. , Donohower , R. C. and Noe , D. A.Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer . Drug. Metab. Dispos. , 20 , 706 – 713 ( 1992 ). [PubMed] [Google Scholar]
  • 18. ) Rowinsky , E. K. , Grochow , L. B. , Hendrichs , C. B. , Ettinger , D. S. , Forastiere , A. A. , Hurowitz , L. A. , McGuire , W. P. , Sartorius , S. E. , Lubejko , B. G. , Kaufmann , S. H. and Donehowere , R. C.Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor . J. Clin. Oncol. , 10 , 647 – 656 ( 1992 ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Rothenberg , M. L. , Kuhn , J. G. , Burris , H. A. , III , Nelson , J. , Eckardt , J. R. , Tristan‐Morales , M. , Hilsenbeck , S. G. , Weiss , G. R. , Smith , L. S. , Rodriguez , G. I. , Rock , M. K. and Von Hoff , D. D.Phase I and pharmacokinetic trial of weekly CPT‐11 . J. Clin. Oncol. , 11 , 2194 – 2204 ( 1993 ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Rowinsky , E. K. , Grochow , L. B. , Ettinger , D. S. , Sartorius , S. E. , Lubejko , B. G. , Chen , T.‐L. , Rock , M. K. and Donehowere , R. C.Phase I and pharmacological study of novel topoisomerase I inhibitor 7‐ethyl‐10‐[4‐(1‐piperidino)‐ 1 ‐piperidino] carbonyloxycamptothecin (CPT‐11) administered as a ninety‐minute infusion every 3 weeks . Cancer Res. , 54 , 427 – 436 ( 1994 ). [PubMed] [Google Scholar]

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