Disposition and Metabolism of ST-630. (3). Dose-response, Effect of Food Intake, Bioavailability after Single Oral Administration, and Serum Concentration, Distribution, Metabolism, Excretion after Single Intravenous Administration of 3H-ST-630 in Rats.

Abstract

The serum concentrations of 3 labeled ST-630 [(+)-(5Z, 7E)-26, 26, 26, 27, 27, 27-hexafluoro-9, 10-secocholesta-5, 7, 10(19)-triene-1α, 3β, 25-triol], a new fluorine-substituted analog of 1α, 25-dihydroxyvitamin D3, were determined in male rats after single oral or intravenous administration at a dose of 0.3, 1.0 or 3 μg/kg. The distribution, metabolism and excretion of 3H labeled ST-630 were also studied in male rats after single intravenous administration at a dose of 0.3 μg/kg. 1. The serum levels of radioactivity reached a maximum (Cmax 614 pg eq./ml) at 2 hr after oral dosing at a dose of 1 μg/kg, and then declined with a half life (t1/2) of 1.6 day (24-168 hr after dosing), the AUC[0-168 hr] was 9.48 ng eq.·.hr/ml. The serum concentrations of ST-630 reached a Cmaxs (620 pg/ml) at 2 hr after oral dosing and then declined with a t1/2 of 20 hr (24-72 hr after dosing), the AUC[0-72 hr] was 6.64 ng·hr/ml. 2. Cmax and AUC of the serum levels of radioactivity and ST-630, after oral dosing showed a good linearity to dose ranging from 0.3 to 3 μg/kg. 3. Cmax and AUC of radioactivi ty and ST-630 after oral dosing to fasting rats were about half of those observed in non-fasting rats. 4. After intravenous dosing at a dose of 0.3 μg/kg, the serum levels of radioactivity declined with a t1/2 of 1.4 day (24-168 hr after dosing), the AUC[0-168 hr] was 15.3 ng eq.·hr/ml, and the serum concentrations of ST-630 declined with a t1/22 of 25 hr (24-120 hr after dosing), and the AUC[0-120 hr] was 13.9 ng·hr/ml. The bioavailability was estimated to be about 17%. 5. The tissue distribution pattern of rad ioactivity after intravenous administration was not significantly different from that after oral dosing, except that the level of the small intestine was lower than that after the oral dosing. 6. The main component of radioactivity in the kidney at 24 hr after intravenous dosing was ST-232, a bioactive metabolite. However, in the small intestine at 24 hr after intravenous dosing, ST-630 was mainly detected. 7. Within 168 hr after intravenous dosing at 0.3 μg/kg, 8.5% and 71.2% of dosed radioactivity were excreted in the urine and feces, respectively.