Does saturable formation of gemcitabine triphosphate occur in patients?

Abstract

The results showed that first-order and nonsaturable clearance described intracellular dFdCTP formation at clinically applied doses of gemcitabine.

Dexmedetomidine pharmacokinetics in the obese

“…The higher concentrations of dexmedetomidine observed in obese patients after receiving TBW-based schemes are explained by two factors: the lack of influence of fat mass on dexmedetomidine volume of distribution and impairment of dexmedetomidine clearance associated with fat mass. This impairment of clearance has not been reported for other drugs examined using either FFM or NFM as a size descriptor (gemcitabine [13], busulphan [20], ethanol [21], paracetamol [22], propofol [23]). The detection of an effect of fat mass on clearance may be due to inclusion of both non-obese and obese patients in our study.…”

“…Standard weight computed from total body weight divided by W STD or NFM STD was then used in an allometric model to predict between subject differences in clearance and volume parameters [13].…”

SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours

“…The concentrations of intracellular dFdCTP were corrected for the mean cell volume of PBMCs to convert the units of concentration from mass per million cells to mass per volume (Cheung et al , 1982). By doing so, dFdCTP was assumed to be uniformly distributed among all of the cells in each sample as done by others (Tham et al , 2008). We tested the estimation of separate residual unexplained variance (RUV) parameters for the HPLC-UV and LC-MS/MS assays used in the analysis of gemcitabine, dFdU and dFdCTP concentrations to account for the differences in their precision and sensitivity.…”

“…A mass-balance study reported that a median of 77% (range: 30–96%) of the administered dose of gemcitabine was excreted within 24 h in urine, of which a median of 5% was excreted as unchanged gemcitabine (Abbruzzese et al , 1991). The pharmacokinetics of dFdCTP has been evaluated in circulating leukaemic cells or peripheral blood mononuclear cells (PBMCs) as a surrogate for tumour (Grunewald, 1990; Tempero et al , 2003; Tham et al , 2008). …”

“…On the basis of these results, others have investigated prolonged gemcitabine infusions to keep the plasma gemcitabine concentrations within 15–20  μ M to maximise the accumulation of dFdCTP. A population pharmacokinetic analysis reported that saturable formation of dFdCTP does not occur at 1000 mg m −2 dose of gemcitabine when administered over 30 min (Tham et al , 2008). Hence, there is evidence both in support as well as against the saturable formation of dFdCTP from gemcitabine.…”