Pharmacokinetic studies of vitamin D analogues: relationship to vitamin D binding protein (DBP).

Vitamin D(3), 25-hydroxyvitamin D(3) (25OHD(3)) and 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)) bind to the vitamin D binding protein (DBP) in the serum. During the development of synthetic vitamin D analogues, it has been shown that the majority of analogues bind to DBP with a low affinity. This modifies their biological activitiesin vitro compared to 1α,25(OH)(2)D(3), since binding to DBP decreases the cellular uptake and access to the vitamin D receptor. It is therefore important to elucidate the possible role played by the binding or lack of binding to DBPin vivo. We have investigated the relationship between the binding affinity for human DBP and the serum level and serum half-life (t(1/2)) in rats of a series of new vitamin D analogues. The binding affinity for DBP was determined by displacement of(3)H-1,25(OH)(2)D(3) from DBP attached to Affi-Gel 10. The serum levels in rats following a single intravenous dose were assessed by HPLC and the serum half-life was determined for each analogue. In the group of vitamin D analogues which showed a low or no affinity for DBP, we have identified compounds with a short t(1/2) and compounds with a long t(1/2), all characterized by low initial serum levels. Compounds with a long t(1/2) were also found in the group with a high affinity for DBP, and they were easily identifiable by their high initial serum level. These results showed that the initial serum level of vitamin D analogues correlated with the affinity for DBP, but that there seemed to be no correlation with the metabolic rate as reflected by measurement of the serum half-life of the analogues.