Abstract
Mitomycin C (MMC) at a dose of 8 mg/m2 was administered by short intravenous infusion to 14 cancer patients. All patients had normal renal, hepatic, cardiac and bone marrow functions. The plasma level of MMC, which was determined by high‐performance liquid chromatography over a 24–h period after the infusion, fitted the 2‐compartment model curve except for one patient. There was a significant correlation between the area under the time versus concentration curve (AUC) of MMC and the age of patients (r= 0.558, P < 0.05). Pharmacokinetic parameters in one of the older (a 69‐year‐old male) patients were extremely different from those of the other 13 patients. This patient experienced severe myelosuppression, probably due to the markedly increased AUC of MMC. Our results suggest that a patient's age has a significant influence on the pharmacokinetics of MMC in patients with normal major organ functions and that in some patients, MMC pharmacokinetics may be altered, possibly due to interpatient variation in the activation or metabolic pathway of MMC.
Keywords: Mitomycin C, Pharmacokinetics, Influence of aging, Interpatient variation
Full Text
The Full Text of this article is available as a PDF (256.8 KB).
REFERENCES
- 1. ) Sasaki , Y. , Fukuda , M. , Morita , M. , Shinkai , T. , Eguchi , K. , Tamura , T. , Ohe , Y. , Yamada , K. , Kojima , A. , Nakagawa , K. , Ohmori , T. and Saijo , N.Prediction from creatinine clearance of thrombocytopenia and recommended dose in patients receiving (glycolato‐O, O')‐diammine platinum (II)(NSC 375101D) . Jpn. J. Cancer Res. , 81 , 196 – 200 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. ) Mayersohn , M.Special pharmacokinetic considerations in the elderly . In “ Applied Pharmacokinetics,” ed. Evans W. E. , Schentag J. J. and Jusko W. J. . pp. 229 – 293 ( 1986. ). Applied Therapeutics, Inc. , Spokane . [Google Scholar]
- 3. ) Wakai , S. , Maruno , H. and Tomioka , K.Isolation of new fractions of antitumor mitomycins . Antibiot. Chemother. , 8 , 228 – 240 ( 1958. ). [PubMed] [Google Scholar]
- 4. ) Zubrod , C. G. , Schneiderman , M. , Frei , E. , Brindley , C. , Gold , G. L. , Shnider , B. , Oviedo , R. , Gorman , J. , Johnes , R. , Jr. , Jonson , U. , Colsky , J. , Chalmers , T. , Ferguson , B. , Dederick , M. , Holland , J. , Selawry , O. , Regelson , W. , Lasagna , L. and Owens , A. H. , Jr. . Appraisal of methods for the study of chemotherapy of cancer in man: comparative therapeutic trial of nitrogen mustard and triethylene thiophosphamide . J. Chronic Dis. , 11 , 7 – 33 ( 1960. ). [Google Scholar]
- 5. ) Fukuoka , E. and Suzuki , K.PHACONET for TDM data analysis . J.J.S.H.P. , 24 , 1201 – 1209 ( 1988. ) ( in Japanese ). [Google Scholar]
- 6. ) Abdallah , H. Y. , Mayersohn , M. and Conrad , K. A.The influence of age on salicylate pharmacokinetics in humans . J. Clin, Pharmacol , 31 , 380 – 387 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Evans , W. J. and Relling , V.Clinical pharmacokinetics‐pharmacodynamics of anticancer drugs . Clin. Pharmacokinet. , 16 , 327 – 336 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 8. ) den Hartigh , J. , van Oort , W. J. , Bocken , M. C. Y. M. and Pinedo , H. M.High‐performance liquid chromatographic determination of the antitumor agent mitomycin C in human blood plasma . Anal. Chim. Acta , 127 , 47 – 53 ( 1981. ). [Google Scholar]
- 9. ) Schilcher , R. B. , Young , J. D. , Ratanatharathorn , V. , Karanes , C. and Baker , L. H.Clinical pharmacokinetics of high‐dose mitomycin C . Cancer Chemother. Pharmacol , 13 , 186 – 190 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 10. ) den Hartigh , J. , McVie , J. G. , van Oort , W. J. and Pinedo , H. M.Pharmacokinetics of mitomycin C in humans . Cancer Res. , 43 , 5017 – 5021 ( 1983. ). [PubMed] [Google Scholar]
- 11. ) Verweij , J. , Stuurman , M. , de Vries , J. and Pinedo , H. M.The difference in pharmacokinetics of mitomycin C., given either as a single agent or as a part of combination chemotherapy . J. Cancer Res. Clin. Oncol , 112 , 283 – 284 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Hashida , M. , Atsumi , R. , Nishida , K. , Nakane , S. , Takakura , Y. and Sezaki , H.Biliary Excretion of mitomycin C dextran conjugates in relation to physicochemical characteristics of carrier dextran . J. Pharmacobio-Dyn. , 13 , 441 – 447 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Hoban , P. R. , Walton , M. I. , Robson , C. N. , Godden , J. , Stratford , I. J. , Workman , P. , Harris , A. L. and Hickson , I. D.Decreased NADPH:cytochrome P‐450 reductase activity and impaired drug activation in a mammalian cell line resistant to mitomycin C under aerobic but not hypoxic conditions . Cancer Res. , 50 , 4692 – 4697 ( 1990. ). [PubMed] [Google Scholar]
- 14. ) Bligh , H. F. J. , Bartoszek , A. , Robson , C. N. , Hickson , I. J. , Kasper , C. B. , Beggs , J. D. and Wolf , C. R.Activation of mitomycin C by NADPH:cytochrome P‐450 reductase . Cancer Res. , 50 , 7789 – 7792 ( 1990. ). [PubMed] [Google Scholar]
- 15. ) Ratain , M. J. and Vogelzang , N. J.Limited sampling models for doxorubicin pharmacokinetics . J. Clin. Oncol. , 9 , 871 – 876 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Egorin , M. J. , Forrest , A. , Belani , C. P. , Ratain , M. J. , Abrams , J. S. and van Echo , D. A.A limited sampling strategy for cyclophosphamide pharmacokinetics . Cancer Res. , 49 , 3129 – 3133 ( 1989. ). [PubMed] [Google Scholar]