Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions.
OBJECTIVE
To examine the effects of fluctuating oxygen levels on the hypoxic cytotoxin tirapazamine (TPZ) using theoretical predictions.


METHODS
Tirapazamine's pharmacokinetic and pharmacodynamic oxygen dependence has previously been characterized in vitro. Here, a one-dimensional theoretical model was used to examine the effects of fluctuating hypoxia on metabolized TPZ concentration, assuming sinusoidally fluctuating oxygen levels. TPZ concentration is changing according to published experimental data. Simulations of experimentally observed time-courses of perivascular pO2 were also conducted.


RESULTS
The predicted pharmacodynamic effect of TPZ was increased with fluctuating (vs. constant) hypoxia at all frequencies (1-30 min period) and all amplitudes (1-15 mm Hg). Additionally, fluctuating oxygen resulted in more metabolized TPZ near the oxygen source as compared with the steady-state condition of the same overall average pO2.


CONCLUSIONS
Fluctuating pO2 reduced the concentration of metabolized TPZ at distances farther from the source, thereby limiting its ability to reach and kill the most hypoxic cells. These results suggest that the kinetics of fluctuating oxygenation should be taken into account when considering drug designs that involve oxygen-sensitive agents.
Cárdenas-Navia
L Isabel
LI
Department of Biomedical Engineering, Duke University, Durham, NC, USA.
Secomb
Timothy W
TW
Dewhirst
Mark W
MW
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D015687:Cell Hypoxia / Q000502:physiology*; D002470:Cell Survival; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D010313:Partial Pressure; D013997:Time Factors; D000077704:Tirapazamine; D014227:Triazines / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D014227:Triazines; D000077704:Tirapazamine; D010100:Oxygen