Disposition and Metabolism of ST-630 (1): Absorption, Distribution and Excretion after Single Oral Administration of ³H-ST-630 in Rats

Abstract

The absorption, distribution and excretion of ³H 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 studied after single oral administration at a dose of 1 or 10 μg/kg in male and female rats.
1. The serum levels of radioactivity reached a maximum (C_max) at about 2 hr after dosing at a dose of 1 μg/kg to male and female rats, and then declined with a half life (t_1/2) of 2.8 day (24 ?? 168 hr after dosing) or 2.0 day (24 ?? 168 hr after dosing) in male and female rats, respectively. The serum concentrations of ST-630 reached a C_max at 2 hr after dosing and then declined with a t_1/2 of 1.0 day (male, 24 ?? 72 hr after dosing) or 0.9 day (female, 24-48 hr after dosing). Most of the radioactivity at 2 hr after dosing was found to be ST-630, and, the ratio of ST-630 to the radioactivity was decreased with time.
2. High levels of radioactivity were detected in the small intestine at 2 ?? 24 hr and in the kidney at 24 hr after dosing at a dose of 1 μg/kg to male and female rats. The autoradiograms of the small intestine showed that the radioactivity was distributed selectively at the intestinal mucosa besides the intestinal contents at 2 ?? 24 hr after dosing with 10 μg/kg to male rats.
3. The ratios of non-volatile radioactive component excluding tritiated water to total radioactivity (dry/wet) in many tissues were decreased with time. However little decrease of dry/wet in the liver, kidney and fat were observed at 168 hr after dosing.
4. Excretion of radioactivities in the urine, feces and expired air were 4.8%, 86.1% and 1.2% respectively for male rats, and 5.0%, 87.9% and 0.8% respectively for female rats within 168 hr after dosing of 1 μg/kg.
5. The t_1/2 and AUC of radioactivity in male rats were about 1.4 times higher than those in female rats. However there were no marked differences in pharmacokinetics of ST-630 between male and female rats. No significant sex-related differences in the distribution and excretion of radioactivity were observed.
6. In bile-duct cannulated rats, 16% of dosed radioactivity was excreted into the bile for 72 hr after dosing at 1 μg/kg, and then approximately 40% of radioactivity presented in the bile was reabsorbed within 48 hr.