Biological potency of a fluorinated vitamin D analogue in hypoparathyroidism

METABOLISM OF 26,26,26,27,27,27-F6-1α,23S,25-TRIHYDROXYVITAMIN D3BY HUMAN UDP-GLUCURONOSYLTRANSFERASE 1A3*

“…26,26,26,27,27,25(OH) 2 D 3 , which is now clinically used as a drug for secondary hyperparathyroidism in cases of chronic renal failure and for the control of hypoparathyroidism (Nakatsuka et al, 1992;Akiba et al, 1998;Inoue and Fujimi, 1998;Mori et al, 1998), is a hexafluorinated analog of the active form of vitamin D 3 . F 6 -1␣,25(OH) 2 D 3 1 has been reported to be several times as potent as the parent compound at increasing intestinal calcium transport and bone calcium (Tanaka et al, 1984;Kiriyama et al, 1991;Inaba et al, 1993).…”

DISPOSITION AND METABOLISM OF F6-1α,25(OH)2 VITAMIN D3 AND 1α,25(OH)2 VITAMIN D3 IN THE PARATHYROID GLANDS OF RATS DOSED WITH TRITIUM-LABELED COMPOUNDS

“…In addition, F 6 -1␣,25(OH) 2 VD 3 administered orally was found to reduce increasing plasma PTH concentrations and PTH mRNA levels in parathyroid-thyroid tissues with therapeutic effects on aberrant bone metabolism in 5/6 nephrectomized rats at lower doses than with 1␣,25(OH) 2 VD 3 (Tsushima et al, 1996). Based on these results, the compound was evaluated for the biological potency and the applicability for clinical control of hypoparathyroidism, secondary hyperparathyroidism, and osteodystrophy in patients with chronic renal failure at lower doses than that of 1␣,25(OH) 2 VD 3 (Nakatsuka et al, 1992;Akiba et al, 1998;Inoue and Fujimi, 1998;Morii et al, 1998).…”

“…The inhibitory effect of F 6 -1␣,25(OH) 2 VD 3 on PTH secretion from parathyroid cells also exceeds that of the parent compound Tsushima et al, 1996;Imanishi et al, 1999). F 6 -1␣,25(OH) 2 VD 3 has been used clinically for the treatment of secondary hyperparathyroidism in cases of chronic renal failure and for the control of hypoparathyroidism (Nakatsuka et al, 1992;Akiba et al, 1998;Inoue and Fujimi, 1998;Morii et al, 1998). The mechanism of action of 1␣,25(OH) 2 VD 3 involves a specific intracellular receptor (vitamin D receptor, VDR), which binds 1␣,25(OH) 2 VD 3 with a high affinity and modulates the transcription of vitamin D responsive genes in the parathyroid glands (Naveh-Many et al, 1990;Demay et al, 1992;Brown et al, 1992bBrown et al, , 1995Hellman et al, 1999).…”

Hexafluoro-1,25-dihydroxyvitamin D3has markedly increased potency in inhibiting proliferation of cultured human keratinocytes compared with 1,25-dihydroxyvitamin D3

“… 23 Furthermore, a clinical study demonstrated that 0·5–1·5 µg daily of F 6 ‐1,25 (OH) 2 D 3 was considered an adequate maintenance dose in various types of hypoparathyroidism, and that changes of medication to the same dose of 1,25(OH) 2 D 3 resulted in a prompt decline of urinary calcium excretion and of whole blood ionized calcium levels, and recurrence of symptoms related to hypocalcaemia, suggesting that F 6 ‐1,25(OH) 2 D 3 had higher biological activities in bone calcium mobilization and was more potent than 1,25(OH) 2 D 3 in correcting hypocalcaemia of hypoparathyroidism. 24 In this report, we describe the biological activity of F 6 ‐1,25(OH) 2 D 3 on cultured normal human and psoriatic keratinocytes.…”

“…Because of the stable carbon–fluoride bond and similar atomic dimension between hydrogen and fluorine, several analogues of 1,25(OH) 2 D 3 with fluorine substitution on the side chain were synthesized, and tested for their biological activities and possible therapeutic applications. 22–24 One of those analogues, hexafluoro‐1,25‐(OH) 2 D 3 (F 6 ‐1,25(OH) 2 D 3 ), was shown to be five times more potent than 1,25(OH) 2 D 3 in healing rickets and elevating serum inorganic phosphorus levels in rachitic rats. It is about 10 times more active than the native hormone in increasing intestinal calcium transport and bone calcium mobilization of vitamin D‐deficient rats fed a low‐calcium diet.…”