Cancer Chemotherapy and Pharmacology

, Volume 27, Issue 4, pp 258–262 | Cite as

Saturation of 2′, 2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine

  • Ralf Grunewald
  • James L. Abbruzzese
  • Peter Tarassoff
  • William Plunkett
Original Articles 2-Difluorodeoxycytidine, Mononuclear Cells, Phase I Trial, Gemcitabine

Summary

The plasma and cellular pharmacology of 2′, 2′-difluorodeoxycytidine (dFdC, Gemcitabine) was studied during a phase I trial. The steady-state concentration of dFdC in plasma was directly proportional to the dFdC dose, which ranged between 53 and 1,000 mg/m2 per 30 min. The cellular pharmacokinetics of an active metabolite, dFdC 5′-triphosphate (dFdCTP), were determined in mononuclear cells of 22 patients by anion-exchange highpressure liquid chromatography. The rate of dFdCTP accumulation and the peak cellular concentration were highest at a dose rate of 350 mg/m2 per 30 min, during which steady-state dFdC levels of 15–20 μM were achieved in plasma. A comparison of patients infused with 800 mg/m2 over 60 min with those receiving the same dose over 30 min demonstrated that the dFdC steady-state concentrations were proportional to the dose rate, but that cellular dFdCTP accumulation rates were similar at each dose rate. At the lower dose rate, the AUC for dFdCTP accumulation was 4-fold that observed at the higher dose rate. Consistent with these observations, the accumulation of dFdCTP by mononuclear cells incubated in vitro was maximal at 10–15 μM dFdC. These studies suggest that the ability of mononuclear cells to use dFdC for triphosphate formation is saturable. In the design of future protocols, a dose rate should be considered that produces maximal nucleotide analogue formation, with increased intensity being achieved by prolonging the duration of infusion.

Abbreviations

ara-C

I-β-d-arabinosylcytosine

ara-Css

steady-state concentration of ara-C

ara-CTP

5′-triphosphate of ara-C

dFdC

2′, 2′-difluorodeoxycytidine, Gemcitabine

dFdCss

steady-state concentration of dFdC

dFdCTP

5′-triphosphate of dFdC

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Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Ralf Grunewald
    • 1
  • James L. Abbruzzese
    • 1
  • Peter Tarassoff
    • 2
  • William Plunkett
    • 1
  1. 1.Department of Medical OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Lilly Research LaboratoriesIndianapolisUSA

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