Contribution of diet to the dosing time-dependent change of vitamin D3-induced hypercalcemia in rats

We have recently reported that the degree of hypercalcemia as an adverse ef fect induced by a single large-dose of active vitamin D3 varied with its do sing time without alteration in therapeutic effect for secondary hyperparat hyroidism in patients with chronic renal failure. The present study was con ducted to elucidate an effect of intestinal calcium (Ca) absorption on the chronophannacological profiles of vitamin D3. I, 25-dihydroxy-cholecalcifer ol (D3, 2 mug/kg) or vehicle alone was orally administered at two different times (2 and 14 hours after lights on; HALO) to male Wistar rats (n=10) ke pt in rooms with a 12 h light-dark cycle. Blood samples for serum Ca concen tration were taken before and 3, 6, 9, and 12 hours after the administratio n. Urine was collected for 6 hours after dosing. An identical protocol was repeated using the same animals after 16 hours fasting by a cross-over fash ion. Under free-fed condition, basal concentration of serum Ca was higher a t a resting period (lights on) than during an active period (lights off). S erum Ca reached its peak at 6 hours after dosing in both timings, while the value was significantly higher in the 2 HALO trial than in the 14 HALO tri al. Area under the serum Ca concentration-time curve from 0 to 12 hours (AU CO-12h) and urinary excretion of Ca for 6 hours were also significantly hig her in the 2 HALO trial than in the 14 HALO trial, when fasted, basal Ca co ncentration was reduced compared with the free-fed condition, while the dai ly variation was maintained. Serum Ca concentration profiles from 3 to 12 h ours after dosing were not significantly different between the 2 HALO and 1 4 HALO trials. The AUCO-12h of serum Ca or its urinary excretion was not di fferent between both trials. Serum concentrations of parathyroid hormone an d total protein, measured before and 6 hours after the dosing were not affe cted by the dosing schedule. We have concluded that intestinal Ca absorptio n is a major factor for the chronopharmacological phenomenon of D3-induced hypercalcemia in intact rats, while intestinal and renal involvement may be relatively small in the mechanism of the intrinsic diurnal variation of se rum Ca. (C) 2000 Elsevier Science Inc. All rights reserved.