| Abstract
| - Background. The therapeutic equivalence of 1,25(OH)2D3 and 1α(OH)D3 on the suppression of PTH synthesis and secretion has not clearly been established. The aim of the present study was to evaluate the pharmacokinetics of 1,25(OH)2D3 and 1α(OH)D3 after oral and i.v. administration in healthy volunteers and uraemic patients. Methods. Six healthy volunteers and 12 uraemic patients were included in the study. With an interval of 2 weeks, 4 μg of 1,25(OH)2D3 i.v., 4 μg of 1,25(OH)2D3 orally, 4 μg of 1α(OH)D3 i.v. and 4 μg of 1α(OH)D3 orally were administered. Blood samples for analysis of plasma-Ca2+, plasma-1,25(OH)2D3, and plasma-PTH were drawn at time 0, 0.25, 0.5, 1, 2, 4, 6, 9, 12, 24, 48, and 72 h. The healthy volunteers were studied in all four protocols and the uraemic patients in either the 1α(OH)D3 (n=6) or the 1,25(OH)2D3 (n=6) protocol. Results. After oral administration of 1,25(OH)2D3 the bioavailability of 1,25(OH)2D3 was 70.6±5.8/72.2±4.8% in healthy volunteers/uraemic patients (n.s.). After i.v. administration the volume of distribution of 1,25(OH)2D3 was similar, 0.49±0.14 vs 0.27±0.06 l/kg in healthy volunteers vs uraemic patients (n.s.), while the metabolic clearance rate of 1,25(OH)2D3 was 57% lower in the uraemic patients, 23.5±4.34 vs 10.1±1.35 ml/min in healthy volunteers vs uraemic patients, respectively (P<0.03). The bioavailability of 1,25(OH)2D3 after i.v. administration of 1α(OH)D3 was 42.4±11.0/42.0±2.0% in healthy volunteers/uraemic patients (n.s.); and after oral administration of 1α(OH)D3 42.0±2.0/29.8±3.1% in healthy volunteers/uraemic patients (n.s.). A small, but significant increase in plasma-Ca2+ was seen after administration of 1,25(OH)2D3 to the uraemic patients, while no increase was seen after administration of 1α(OH)D3. PTH levels were significantly suppressed in the healthy volunteers 24 h after administration of 4 μg of 1,25(OH)2D3 i.v., 4 μg of 1,25(OH)2D3 orally, and 4 μg of 1α(OH)D3 orally by 35±7, 30±8, and 35±4%, respectively (all P<0.03). In the uraemic patients, PTH levels were significantly suppressed after administration of 4 μg of 1,25(OH)2D3 i.v., 4 μg of 1,25(OH)2D3 orally, and 4 μg of 1α(OH)D3 i.v. by 30±10, 45±7, and 40±7%, respectively (all P<0.04). The effect was transitory in the healthy volunteers and lasted for at least 72 h in the uraemic patients. Conclusion. The present study found a 57% lower metabolic clearance rate of 1,25(OH)2D3 in uraemic patients, as compared with that of healthy volunteers (P<0.03). The bioavailability of 1,25(OH)2D3 following administration of 1α(OH)D3 i.v. and orally in both healthy volunteers and uraemic patients was markedly lower than after administration of oral 1,25(OH)2D3 (P<0.03). In spite of lower plasma-1,25(OH)2D3 levels after administration of 1α(OH)D3, no significant difference was observed on the suppressive effect of 4 μg i.v. of either 1,25(OH)2D3 or 1α(OH)D3 on the plasma-PTH levels in the uraemic patients. This might suggest the existence of an effect of 1α(OH)D3 on the parathyroid glands which is independent of the plasma-1,25(OH)2D3 levels, that are achieved after oral or i.v. administration of 1α(OH)D3.
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