Norethindrone disposition following x-ionizing radiation in rats

The pharmacokinetics of norethindrone were investigated in rats exposed to ionizing x-irradiation. Norethindrone was administered by IV bolus injection immediately after, 3 days or 7 days after exposure to 100 rads, 300 rads, 600 rads, and sham x-irradiation. No observable change in norethindrone pharmacokinetics was observed in rats immediately after exposure to all dose levels of x-rays. At three days post irradiation there was an increase in volume of distribution (Vdarea) from 5.55 +/- 0.93 l/kg for sham irradiated to 11.28 +/- 0.74 l/kg for 600 rad rats. Half-life increased after exposure to x-rays from 45.2 +/- 4.5 minutes for sham irradiated to 85.5 +/- 12.1 minutes for 600 rads dose. The Mean Residence Time (MRT) increased from 56.7 +/- 5.6 minutes to 96.4 +/- 13.6 minutes after exposure to 600 rads. This same trend was present 7 days post irradiation but was not nearly as pronounced. No significant differences were observed in total body clearance in irradiated versus sham irradiated animals. As norethindrone is excreted as metabolites via hepatic biotransformation, these findings imply that this process is not affected by irradiation for drugs with high hepatic extraction ratios. Increased distribution of norethindrone to peripheral tissues results in a longer MRT for irradiated animals which could result from radiation induced increase in membrane permeability