Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1990 Nov;62(5):766–772. doi: 10.1038/bjc.1990.376

Pharmacokinetic studies with the antifolate C2-desamino-C2-methyl-N10-propargyl-2'-trifluoromethyl-5,8-dideazafolic acid (CB3988) in mice and rats using in vivo 19F-NMR spectroscopy.

D R Newell 1, R J Maxwell 1, G M Bisset 1, D I Jodrell 1, J R Griffiths 1
PMCID: PMC1971528  PMID: 2245168

Abstract

In vivo 19F-NMR spectroscopy has been used to study the pharmacokinetics of the experimental antifolate drug CB3988 (C2-desamino-C2-methyl-N10-propargyl-2'trifluoromethyl-5,8-dideazafolic acid) in mice and rats. NMR results have been compared to those obtained by HPLC and the effect of the inclusion of the CF3 group evaluated by comparing the pharmacokinetics of CB3988 and ICI 198583 (C2-desamino-C2-methyl-N10-propargyl-5,8-dideazafolic acid) in rats. In mice, following the administration of CB3988 (500 mg kg-1 i.v.), drug could be detected in both the upper and the lower abdomen. NMR signal from the upper abdomen reached maximum intensity 10-40 min after administration, declining thereafter with a half life of 28 min. Signal detected in the lower abdomen reached maximum intensity 60-90 min after treatment. HPLC analyses indicated that CB3988 was present at appreciable concentrations (about 20-30 mg ml-1) in both bile and urine which is consistent with the signal from the upper and lower abdomen being derived from the gall bladder and urinary bladder, respectively. Studies in rats also indicated that CB3988 (100 mg kg-1 i.v.) rapidly entered and was cleared from the upper abdomen. Comparison of data from rats with intact and cannulated bile ducts suggested that 19F-NMR could detect CB3988 undergoing enterohepatic circulation. Furthermore, comparison of the plasma half life of CB3988 with the half life for the decline of the NMR signal from the upper abdomen suggested that NMR measurements may reflect the plasma clearance of CB3988. When the pharmacokinetics of CB3988 and ICI 198583 were compared the only significant difference was in the alpha phase half life which was 2-fold faster for CB3988. These data demonstrate that CB3988 is cleared rapidly by both biliary and urinary excretion. This is in contrast to N10-propargyl-5,8-dideazafolic acid, where delayed excretion is associated with hepatic and renal toxicities. The ability to study CB3988 pharmacokinetics non-invasively by 19F-NMR spectroscopy confirms the utility of the technique and, since 19F-NMR can be applied directly to clinical investigations, it may be possible to obtain similar information in humans.

Full text

PDF
766

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alison D. L., Newell D. R., Sessa C., Harland S. J., Hart L. I., Harrap K. R., Calvert A. H. The clinical pharmacokinetics of the novel antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717). Cancer Chemother Pharmacol. 1985;14(3):265–271. doi: 10.1007/BF00258131. [DOI] [PubMed] [Google Scholar]
  2. Calvert A. H., Alison D. L., Harland S. J., Robinson B. A., Jackman A. L., Jones T. R., Newell D. R., Siddik Z. H., Wiltshaw E., McElwain T. J. A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717. J Clin Oncol. 1986 Aug;4(8):1245–1252. doi: 10.1200/JCO.1986.4.8.1245. [DOI] [PubMed] [Google Scholar]
  3. Griffin D., Said H. M. The enterohepatic circulation of methotrexate in vivo: inhibition by bile salt. Cancer Chemother Pharmacol. 1987;19(1):40–41. doi: 10.1007/BF00296253. [DOI] [PubMed] [Google Scholar]
  4. Hull W. E., Port R. E., Herrmann R., Britsch B., Kunz W. Metabolites of 5-fluorouracil in plasma and urine, as monitored by 19F nuclear magnetic resonance spectroscopy, for patients receiving chemotherapy with or without methotrexate pretreatment. Cancer Res. 1988 Mar 15;48(6):1680–1688. [PubMed] [Google Scholar]
  5. Keniry M., Benz C., Shafer R. H., James T. L. Noninvasive spectroscopic analysis of fluoropyrimidine metabolism in cultured tumor cells. Cancer Res. 1986 Apr;46(4 Pt 1):1754–1758. [PubMed] [Google Scholar]
  6. Manteuffel-Cymborowska M., Sikora E., Grzelakowska-Sztabert B. Polyglutamation of the antifolate anticancer drug N10-propargyl-5,8-dideazafolic acid (CB 3717) in the mouse. Anticancer Res. 1986 Jul-Aug;6(4):807–812. [PubMed] [Google Scholar]
  7. Maxwell R. J., Workman P., Griffiths J. R. Demonstration of tumor-selective retention of fluorinated nitroimidazole probes by 19F magnetic resonance spectroscopy in vivo. Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):925–929. doi: 10.1016/0360-3016(89)90888-2. [DOI] [PubMed] [Google Scholar]
  8. Newell D. R., Alison D. L., Calvert A. H., Harrap K. R., Jarman M., Jones T. R., Manteuffel-Cymborowska M., O'Connor P. Pharmacokinetics of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) in the mouse. Cancer Treat Rep. 1986 Aug;70(8):971–979. [PubMed] [Google Scholar]
  9. Newell D. R. Pharmacokinetic determinants of the activity and toxicity of antitumour agents. Cancer Surv. 1989;8(3):557–603. [PubMed] [Google Scholar]
  10. Selinsky B. S., Perlman M. E., London R. E. In vivo nuclear magnetic resonance studies of hepatic methoxyflurane metabolism. I. Verification and quantitation of methoxydifluoroacetate. Mol Pharmacol. 1988 May;33(5):559–566. [PubMed] [Google Scholar]
  11. Selinsky B. S., Perlman M. E., London R. E. In vivo nuclear magnetic resonance studies of hepatic methoxyflurane metabolism. II. A reevaluation of hepatic metabolic pathways. Mol Pharmacol. 1988 May;33(5):567–573. [PubMed] [Google Scholar]
  12. Selinsky B. S., Thompson M., London R. E. Measurements of in vivo hepatic halothane metabolism in rats using 19F NMR spectroscopy. Biochem Pharmacol. 1987 Feb 15;36(4):413–416. doi: 10.1016/0006-2952(87)90344-3. [DOI] [PubMed] [Google Scholar]
  13. Sikora E., Jackman A. L., Newell D. R., Calvert A. H. Formation and retention and biological activity of N10-propargyl-5,8-dideazafolic acid (CB3717) polyglutamates in L1210 cells in vitro. Biochem Pharmacol. 1988 Nov 1;37(21):4047–4054. doi: 10.1016/0006-2952(88)90094-9. [DOI] [PubMed] [Google Scholar]
  14. Stevens A. N., Morris P. G., Iles R. A., Sheldon P. W., Griffiths J. R. 5-fluorouracil metabolism monitored in vivo by 19F NMR. Br J Cancer. 1984 Jul;50(1):113–117. doi: 10.1038/bjc.1984.146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Vialaneix J. P., Malet-Martino M. C., Hoffmann J. S., Pris J., Martino R. Direct detection of new flucytosine metabolites in human biofluids by 19F nuclear magnetic resonance. Drug Metab Dispos. 1987 Sep-Oct;15(5):718–724. [PubMed] [Google Scholar]
  16. Wolf W., Albright M. J., Silver M. S., Weber H., Reichardt U., Sauer R. Fluorine-19 NMR spectroscopic studies of the metabolism of 5-fluorouracil in the liver of patients undergoing chemotherapy. Magn Reson Imaging. 1987;5(3):165–169. doi: 10.1016/0730-725x(87)90016-6. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES