Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine

In summary, there are compelling laboratory and clinical data indicating that higher doses of ara-C than are currently used in SDaC protocols constitute optimal therapy. The cellular pharmacokinetics of ara-C are optimized at extracellular drug concentrations in the 10 to 15 mumol/L range. At these concentrations, transport rates are no longer rate-limiting, and ara-C phosphorylation capacity is saturated. The prime determinants of ara-C effect then shift to multiple intracellular events including anabolism to nucleotides, catabolism via deamination by Cyd-dCyd deaminase and dCMP deaminase, half-life of ara-CTP, the extent of incorporation into DNA, and the half-life of ara-CMP residues in DNA. It is postulated that at these high doses an additional effect of ara-C occurs on the cell membrane through affects on membrane phospholipid synthesis. This effect may contribute to the brisk cell lysis associated with HiDaC treatment. When administered as repetitive doses of 3 g/m2 over a 1- to 3-hour period, systemic deamination of ara-C gives rise to high plasma concentrations of ara-U. This metabolite has a long plasma half-life and, at least in the mouse, is concentrated in the liver and kidneys. High concentrations in these organs retard the further catabolism of ara-C and thus increase the systemic AUC providing a longer exposure period to the drug. A similar mechanism may obtain in patients treated with HiDaC. The observed decreased clearance of ara-C when administered in gram versus milligram doses and the long-terminal gamma-phase in plasma clearance of the drug associated with HiDaC usage quite probably reflects this effect of ara-U in patients. Additionally, by some as yet unknown mechanism, high concentrations of ara-U cause accumulation of leukemia cells in S-phase, the phase of the cell cycle wherein ara-C is maximally effective. This effect of ara-U may add to the cytokinetic effects initiated by rapid cytoreduction, which summate in the observed enhancement of the proliferative fraction of residual leukemia cells on day 8. The effect of a second course of therapy at this time is thereby enhanced. These dose-related and metabolite-drug interactions that occur when ara-C is given at high doses constitute a means for "self-potentiation" and may thus contribute to its overall therapeutic efficacy.