THE "D" VITAMINS

Jack DeRuiter

I. INTRODUCTION AND BIOSYNTHESIS

In a classical sense, vitamin D3, the form produced in animals, is not a true “vitamin”
because it is produced in the skin from 7-dehydrocholesterol by UV radiation in the range
290 to 300 nm; 7-dehydrocholesterol is produced from cholesterol metabolism. Only
when exposure to sunlight is inadequate does vitamin D3 become a vitamin in the
historical sense. Further, vitamin D3 is now termed a provitamin because it requires
hydroxylation by the liver and the kidney to be fully active.
Upon UV irradiation, 7-dehydrocholesterol is converted rapidly to previtamin D3 (Figure
1). Previtamin D3 undergoes a slow thermal conversion to vitamin D3 and the biologically
inactive lumisterol3 and tachysterol3. This provides a mechanism to prevent an
overproduction of vitamin D3 with an overexposure to sunlight, while providing a means
for an adequate supply of the vitamin when exposure to sunlight is short. Excess
exposure increases production of the inactive compounds. The slow conversion of
previtamin D3 to vitamin D3 ensures adequate supplies when the exposure is brief.
Further, lumisterol and tachysterol can be converted back to previtamin D3, thus serving
as a reservoir. It has been estimated that a 10-minute exposure of just the uncovered
hands and face suffices to produce sufficient vitamin D3 (Figure 1).
The mechanism responsible for the movement of vitamin D3 from the skin to the blood is
not known. In the blood vitamin D3 is bound primarily to a protein known as vitamin D-
binding protein (VDBP). This protein selectively removes vitamin D3 from the skin
because it has low affinity for 7-dehydrocholesterol, previtamin D3, lumisterol and
tachysterol (Figure 2).
Cholecalciferol (vitamin D3) does not perform its function, directly but must first be
transformed by the liver and the kidney. The first step occurs in the liver by the enzyme
vitamin D3-25-hydroxylase. This enzyme converts the provitamin to 25-hydroxyvitamin-
D3 (25-OH D3). This enzyme, requiring both molecular oxygen and reduced nicotinamide
adenine nucleotide phosphate (NADPH), appears to be a cytochrome-P450
monooxygenase and is found in the endoplasmic reticulum and the mitochondria. The
rate of this hydroxylation correlates with substrate concentration. The 25-OH D3 thus,
formed is the major circulating form of the vitamin bound to VDBP (Figure 1).

The epithelial cells of renal proximal convoluted tubules convert 25-OH D3 to1α,25-OH
D3 by the enzyme 25-OHD 1α-hydroxylase. The activity of this mitochondrial
cytochrome P450 enzyme is controlled by lα,25-OH D3 and parathyroid hormone as well
as high concentrations of calcium and phosphate.

The second reaction of activation, 24-hydroxylation proceeds in the kidney, and this
initiates inactivation. lα,25-OH D3 can bring about the appearance of the 24-hydroxylase
system that catalyzes its metabolic inactivation. The need for calcium stimulates
parathyroid hormone secretion. Parathyroid hormone in turn suppresses the 24-
 CH3 CH3
CH3 CH3 CH3 CH3
CH3
CH3 CH3 CH3
CH3 CH3
CH3
CH3 hv
(290-300 nm)

HO
HO HO
Cholesterol Previtamin D3
7-Dehydrocholesterol
(Provitamin D3)

CH3 CH3 CH3 CH3

CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
CH3
CH2

HO HO
HO
Lumisterol3 Tachysterol3
Cholecalciferol
(Vitamin D3)

CH3 CH3 CH3 CH3

CH3 CH3
OH
CH3 CH3
OH CH3
CH3 CH3
CH3

Vitamin D3
25-hydroxylase 25-OH-Vitamin D3-1-hydroxylase
O2 NADPH (Kidney Mitochondria)
CH2 (Liver Mitochondria) CH2
CH2

HO HO OH
HO
Calcifediol Calcitriol
(25-Hydroxyvitamin D3)
(1α,25-Dihydroxyvitamin D3)

1α,25-Dihydroxyvitamin D3-24-hydroxylase
(Kidney Mitochondria)

CH3 CH3
CH3
OH
CH3

OH

CH 2

HO OH

(1α,24,25-Trihydroxyvitamin D3)
Inactive
Figure 1: Vitamin D biosynthesis, Activation and Inactivation
hydroxylase and stimulates the 1α-hydroxylase system. When phosphate availability is
below normal, the 1α-hydroxylase is stimulated and the 24-hydroxylase undergoes
suppression.

II. RECEPTOR BINDING AND PHYSIOLOGIC ACTIONS

As with vitamin A, most of the effects of vitamin D involve a nuclear receptor. The
vitamin D receptor is a member of the steroid/thyroid hormone superfamily of receptors.
When 1α,25-OH D3 binds to its receptor, the complex forms a heterodimer with an
unoccupied RXR. This heterodimer subsequently binds to the regulatory regions on
specific genes in target tissue. These regions are called vitamin D response elements
(VDREs). The binding to VDREs can increase or decrease expression of genes. The
proteins thus made carry out the functions of vitamin D.
The physiologic role of vitamin D is to maintain calcium homeostasis. Phosphate
metabolism also is affected. Vitamin D accomplishes its role by enhancing the absorption
of calcium and phosphate from the small intestines, promoting their mobilization from
bone, and decreasing their excretion by the kidney. Also involved are parathyroid
hormone and calcitonin.
1α,25-OH D3 promotes Ca2+ intestinal absorption and increases Ca2+ renal reabsorption
in the distal tubules and mobilization of Ca2+ from bone. The mechanism of action
promoting Ca2+ transport in the intestine involves formation of a calcium-binding protein.
1α, a,25-OH D3 promotes availability of this protein. A calcium-dependent ATPase, Na+,
and the calcium-binding protein are necessary for the intestinal Ca2+-transport process.
1α,25-OH D3 also promotes intestinal phosphate absorption, mobilization of Ca2+ and
phosphate from bone, and renal reabsorption of Ca2+ and phosphate. Vitamin D
deficiency results in rickets in infants and children as a result of inadequate calcification
of bones. In adults, osteomalacia most often occurs during pregnancy and lactation.
Rickets is rare in the United States due to fortification of foods. However, deficiencies in
the elderly are the result of underexposure to sunlight.
Hypervitaminosis D may result from large doses of the vitamin or from a hypersensitivity
to the vitamin. Early symptoms are associated with hypercalcemia, including fatigue,
weakness, nausea, vomiting, vertigo, and bone pain. Prolonged hypercalcemia may result
in calcium deposits in the kidneys, vessels, heart, lungs, and skin. Treatment includes
withdrawal of the vitamin and a low-calcium diet with an increase in fluids.
Ergocalciferol (vitamin D2) is produced in plants from ergosterol upon UV irradiation.
Vitamin D2 is the form most often used in commercial products and to fortify foods. Al-
though different in structure, its biologic activity is comparable to that of vitamin D3 and
must be bioactivated in a similar fashion (Figure 3). Ergosterol (precursor of D2) occurs
naturally in fungi and yeast. Eggs and butter contain vitamin D2 (ergocalciferol) or D3
(cholecalciferol). Milk and bread are fortified with vitamin D2-cholecalciferol is found in
fish liver oils.
The gastrointestinal absorption of the vitamin Ds requires bile. Vitamin D3 may be
absorbed better than vitamin D2. The vitamin Ds enters the circulation through lymph
chylomicrons. In the blood they are associated with vitamin D-binding protein (VDBP).
The 25-hydroxylated compounds are the major circulating metabolites. These may be
stored in fats and muscle for prolonged periods. The 24-hydroxy metabolites are excreted
primarily in the bile.

CH3 CH3 CH3 CH3

CH3 CH3
CH3 CH3
CH3 CH3 hv CH2 CH3
(290-300 nm)

HO HO
Ergosterol Ergocalciferol
(Provitamin D2) (Vitamin D2)

CH3 CH3 CH3 CH3

CH3
OH CH3
CH3 CH3

CH3 Vitamin D3 CH3

25-hydroxylase
O2 NADPH
(Liver Mitochondria)
CH 2 CH 2

HO HO
25-Hydroxyergocalcifediol
(25-Hydroxyvitamin D2)

25-OH-Vitamin D3-1-hydroxylase
(Kidney Mitochondria)

CH3 CH3
CH3
OH
CH3
CH3

CH 2

HO OH

1α,25-Dihydroxyergocalciferol)
(1α,25-Dihydroxyvitamin D2)

Figure 3: Ergosterol and Vitamin D2 metabolism

The vitamin Ds are important in the therapeutics of hypoparathyroidism and of vitamin D
deficiency. Ergocalciferol, cholecalciferol, and dihydrotachysterol are recognized by the
USP. Although dihydrotachysterol has relatively weak antirachitic activity, it is effective
and quicker acting in increasing serum Ca2+ concentrations in parathyroid deficiency.
Dihydrotachysterol has a shorter duration of action; hence, it has less potential for
toxicity from hypercalcemia.
Vitamin D receptors have been identified in tissue not normally associated with bone
mineral homeostasis. Besides the intestines, kidneys, and osteoblasts, vitamin D receptors
have been located in the parathyroid gland, the pancreatic islet cells, the mammary
epithelium, and the skin keratinocytes. This has resulted in many investigational uses for
vitamin D, including suppression of parathyroid hormone and treatment of colon and
breast cancers and psoriasis. The previously mentioned investigational treatments re-
quire high doses of vitamin D. The resultant hypercalcemia and hypercalciuria limit the
use of vitamin D natural metabolites. Vitamin D analogues with a decreased tendency to
cause hypercalcemia and hypercalciuria are being developed and investigated. These
analogues have low affinity for VDBP but retain high affinity for the vitamin D
receptors. The only approved use of a vitamin D analogue is in the treatment of psoriasis
with calcipotriene.

III. VITAMIN D PRODUCTS

Ergocalciferol, USP. 9,10-Secoergosta-5,7,10(19),22-tetraden-3-ol (3,6,5z,7E,22E);

vitamin D2; calciferol; activated ergosterol. One USP or International unit is 0.025 µg of
vitamin D3. Thus, 1 µg equals 40 USP units. Because ergocalciferol is the least expensive
of the vitamin D analogues, it is the preferred drug, unless the patient is unable to activate
it. After irradiation, the steroid undergoes fission of ring B; therefore, it is known as a
secosteroid. This is indicated name by the “9,10-seco” portion. The “ergosta" indicates
the presence of 28 atoms in the carbon skeleton.

Ergocalciferol has a half-life of 24 hours (19 to 48 hours) and a duration of action of up

to 6 months. After oral intramuscular administration, the onset of action (hypercalcemia)
is 10 to 24 hours, with maximal effects seen 4 weeks, after daily administration.

Vitamin D2 is a white, odorless, crystalline compound that is soluble in fats and in the
usual organic solvents including alcohol. It is insoluble in water. Vitamin D2 is oxidized
slowly in oils by oxygen from the air, probably through the fat peroxides that are formed.
Vitamin A is much, less stable under the same conditions.

Cholecalciferol, USP. 9,10-secocholesta-5,7,10(19)-trien-3-ol (3,8,SZ,7E); vitamin D3;

activated 7-dehydrocholesterol. It occurs as white, odorless crystals that are soluble in
fatty oils, alcohol, and many organic solvents. It is insoluble in water. Vitamin D3 also
occurs in tuna and halibut liver oils. It humans both vitamins have equal activity.

Vitamin D3 exhibits stability comparable with vitamin D2. Epimerization of the -OH at C-
3 in vitamin D2 or D3 Or conversion of the—OH at C-3 to a ketone group greatly
 diminishes the activity but does not completely destroy it. Ethers and esters that cannot
be cleaved in the body have no vitamin D activity. Inversion of the hydrogen at C-9 in
ergosterol and other 7-dehydrosterols prevents the normal course of irradiation.
Dihydrotachysterol (Hytakerol): Also known as 9,10-Ergosta-5,7,22-trien-3-ol
(3,6,5E,7E,10α,22E); dihydrotachysterol2; dichysterol; DHT. Tachysterol is a by-product
of ergosterol irradiation. Reduction of tachysterol led to dihydrotachysterol.
Dihydrotachysterol occurs as colorless or white crystals or a while, crystalline, odorless
powder. It is soluble in alcohol, freely soluble in chloroform, sparingly soluble in
vegetable oils, and practically insoluble in water.

CH3 CH3 CH3

CH3 CH3 CH3
CH3 OH
CH3 CH3 CH3
CH3 CH3
CH3 CH3
CH3

CH3 CH3
CH3

HO HO
HO
Tachysterol2 Dihydrotachysterol2 25-Dihydroxydihydrotachysterol2

Dihydrotachysterol has slight antirachitic activity. It causes an increase of the calcium

concentration in the blood, an effect for which tachysterol is only one-tenth as active. In
high doses, dihydrotachysterol is more effective than the other analogues for the
mobilization of calcium. Thus, it is used in hypoparathyroidism.
After oral administration, the onset of action is seen within hours. This fast onset of
action is an advantage of this drug. Maximal activity is seen in 2 weeks after daily
administration. Its duration of action is 2 weeks.
Dihydrotachysterol is converted by hepatic enzymes to its active 25-hydroxylated
metabolite. It does not require renal activation, for the hydroxy on ring A occupies the
same position as that of the 1-hydroxyl in the activated forms of the vitamin Ds. 25-
Hydroxydihydrotachysterol3 has weak antirachitic activity, but it is a more important
bone-mobilizing agent and is more effective than dihydrotachysterol3. Also, it is more
effective in increasing intestinal calcium transport and bone mobilization in
thyroparathyroidectornized rats. Its activity suggests that it may be the drug of choice in
the treatment of hypoparathyroidism and similar bone diseases.
Calcifediol, USP. 9,10-Secocholesta-5,7,10(19)-trien-3,25-diol (3,6,5Z,7E); 25-hydroxy-
cholecalciferol; 25-hydroxyvitamin D3. Calcifediol occurs as a white powder. It is
practically insoluble in water and sensitive to light and heat. The half-life of calcifediol is
16 days (10 to 22 days). Its onset of action is seen within 2 to 6 hours, and its duration of
action is 15 to 20 days. Calcifediol is indicated for patients receiving long-term renal
dialysis.
 Calcitrol. 9,10-Secocholesta-5,7,10(19)-trien-1,3,25-triol (1α,3,8,5Z,7E); 1,25-
dihydroxycholecalciferol; 1,25-dihydroxyvitamin D3. It occurs as colorless crystals that
are insoluble in water. Since calcitriol does not require activation, an increase in calcium
absorption is seen within 2 hours of administration. Its half-life is 3 to 8 hours, and its
duration of action is 1 to 2 days. Calcitriol is the most active form of vitamin D3. It is
indicated in patients receiving long-term renal dialysis or who cannot properly
metabolize ergocalciferol.
Calcipotriene. 9,10-Secochola-5,7,10(19),22-tetraien-1,3,25-trio-1,24-cyclopropyl-
(1α,3,6,5Z,7E,22E,24S); calcipotriol. Calcipotriene is a synthetic vitamin D3 analogue
indicated for topical application in the treatment of moderate plaque psoriasis. It has the
same affinity for the vitamin D receptor as calcitriol, but its effect on calcium metabolism
is 100 to 200 times less. Calcipotriene inhibits epidermal cell proliferation and enhances
cell differentiation. It reduces cell ‘numbers and total DNA content. Antiproliferative
effects are caused by a reduction in the mRNA levels of a cellular oncogene associated
with proliferation, c-myc. The mechanism resulting in differentiation changes is not
completely known but involves the secondary messengers inositol triphosphate (IP3) and
diacylglycerol (DAG).
CH3 OH
CH3

CH2

HO OH

Calcipotriene

IV. NEW VITAMIN D PRODUCTS

A. Paricalcitol (Zemplar®)

Hyperparathyroldism is a frequent complication of chronic renal failure and requires close

monitoring and treatment to prevent the complications of renal osteodystrophy. Therapy includes
prevention of hyperphosphatemia by the administration of phosphate binders (calcium carbonate
or acetate) and the use of vitamin D compounds such as calcitriol. For patients on hemodialysis
intravenous calcitriol achieves effective suppression of elevated parathyroid hormone (PTH)
levels. However, hypercalcemia and/or hyperphosphatemia are frequent complications that limit
the calcitriol therapy. The newly approved synthetic vitamin D analogue paricalcitol appears to
represent a more effective agent to control secondary hyperparathyroidism associated with end-
stage renal disease since it suppresses intact PTH (IPTH) levels with less impact on calcium and
phosphorus metabolism. Studies in animals suggest that paricalcitol and calcitriol have different
dose-response profiles and mechanisms with respect to the regulation of intestinal vitamin D
receptor (VDR) content, parathyroid gland growth and bone resorption. For example, while
calcitriol and paricalcitol have nearly the same vitamin D binding protein affinity and circulating
half-life, only calcitriol significantly upregulates the intestinal VDR content at therapeutic doses.
Also at therapeutic levels paricalcitol reduces parathyroid gland weight while calcitriol does not.
Finally plasma calcium and phosphorus levels are lower in animals treated with paricaclitol
compared to those treated with the same dose of calcitriol. Overall, paricalcitol is approximately
ten-fold less active than calcitriol in promoting calcium and phosphorus resorption from the
bone.

Paracalcitol has been shown to be safe and effective in reducing serum PTH levels in
hemodialysis patients with secondary hyperparathyroidism associated with chronic renal failure.
In general the side effect profile of paricalcitol is similar to that of calcitriol with the most
common adverse reactions including nausea (13%), vomiting (8%), and edema (7%). Other
adverse events observed in greater than 2% of the trial population included GI bleeding,
pneumonia, chills, fever and flu, sepsis, lightheadedness, dry mouth, palpitation and
miscellaneous cardiovascular and CNS effects. Of course, overdosage of paricalcitol may cause
hypercalcemia with early symptoms including weakness, headache, somnolence, nausea,
vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste. To avoid
paricalcitol overdosing, serum calcium and phosphorus levels should be monitored closely.
Paricalcitol doses should be reduced or therapy interrupted if symptoms of hypercalcemia are
confirmed.

No specific drug interaction studies have been performed on paricalcitol. However, because of
the risk of hypercalcemia in patients receiving paricalcitol, caution should be exercised when this
drug is used in patients also receiving digoxin.

Bolus doses of 0.24 mcg/kg in CRF patients provides peak paricalcitol levels of 1850 pg/mL
within 5 minutes. Plasma levels decrease rapidly within the first two hours after injection, and
then decline in a log-linear manner with a mean half-life of about 15 hours. No accumulation of
drug was observed after multiple dosing. Mean AUC, clearance and steady-state volume of
distribution are 27,382 pg.hr/mL, 0.72 L/hr and 6 L, respectively. Plasma protein binding, in
vitro, was >99.9%. Paricalcitol is eliminated primarily by hepatobiliary excretion with 74% of
the dose recovered in feces and only 16% in urine. Several metabolites of undetermined structure
have been detected in urine and feces and account more than 50% of the dose recovered. The
effects of age and hepatic status on pharmacokinetics remains to be determined.

Paricalcitol is supplied as a 5 mcg/ml injection form in 1 or 2 ml single dose fliptop vials. The
recommended initial dose is a 0.04 mcg/kg to 0.1 mcg/kg bolus dose no more than every other
day during dialysis. The dose may be increased by 2 to 4 mcg at 2 to 4 week intervals if initial
response is not satisfactory. Doses as high as 0.24 mcg/kg (16.8 mcg) have been safely
administered. During any dose adjustment period, serum calcium and phosphorus levels should
be monitored more frequently, and if an elevated calcium level or a Ca x P product of greater
than 75 is noted, drug doses should be reduced immediately or therapy interrupted until
parameters are normalized. Drug therapy can be reinitiated at a lower dose after normalization of
levels. Doses may need to be decreased as the PTH levels decrease in response to therapy. Thus,
individualize incremental dosing and the manufacturer’s literature should be consulted for dose
titration. To ensure effectiveness of paricalcitol therapy, patients must adhere to a dietary
regimen of calcium supplementation and phosphorus restriction. At present there are no
adequate and well controlled studies in pregnant women. However, in animal studies high doses
of paricalcitol there was a significant increase in fetal mortality linked to maternal
hypercalcemia. Thus use of paricalcitol during pregnancy is advised only if the potential benefit
justifies the potential risk to the fetus. Also, since it is not known whether paricalcitol is
excreted in breast milk, caution should be exercised when paricalcitol is administered to nursing
women.

CH3 CH3
CH3 CH3
OH
CH3

HO OH

Paricalcitol

B. Doxercalciferol (Hectorol® - Bone Care International)

In recent years there has been considerable interest in developing vitamin D analogues
that have PTH suppressive actions comparable to calcitriol, but a lower incidence of
hypercalcemia or hyperphosphatemia. Over the past several years two products with
such properties have been introduced in the US, paricalcitol (Zemplar) last year and
doxercalciferol this year. Doxercalciferol is the 1α-hydroxy analogue of ergocalciferol
(Vitamin D2), the plant vitamin which yields hormones of activity comparable to
calcitriol upon metabolic activation. Since it already contains a hydroxyl function at the
1-position, doxercalciferol requires oxidation by only hepatic (not renal) enzymes to yield
an active hormone, 1α,25-dihydroxy vitamin D2. In animal models doxercalciferol is
equipoptent to most other vitamin D analogues in stimulating intestinal calcium transport,
mobilizing calcium from bone and healing vitamin D-related disease states such as
ricketts. Furthermore, much higher doses of doxercalciferol are required to produce
hypercalcemia, according to animal and human studies. At present it is not clear why
doxercalciferol displays greater selectivity compared with calcitriol and other vitamin D
products.

Doxercalciferol is indicated for the treatment of secondary hyperparathyroidism in end-

stage renal disease. The dose of doxercalciferol must be individualized and based on
intact parathyroid hormone (iPTH) levels with monitoring of serum calcium and serum
phosphate levels. In one of the largest trials in patients with moderate-to-severe
hyperparathyroidism doxercalciferol doses of 10 micrograms (mcg) three times weekly
(after dialysis initially), followed by dose adjustments, were found to maintain serum
PTH levels of 150-300 pg/mL in most patients. Final doses ranged from less than 2.5 to
28 mcg per hemodialysis. Therapy was administered for a total of 16 weeks and patients
received phosphate binders (calcium carbonate or acetate) to maintain serum phosphorus
levels of less than 2.2 mmol/L. In another study a doxercalciferol dose of 4 mcg daily
was comparable in efficacy and safety to 10 mcg three times weekly. In an 8-week,
double-blind continuation of two open label studies, patients continuing on
doxercalciferol maintained their reduced levels of iPTH, whereas iPTH rose again in
patients taking placebo. In most studies mean increases in serum calcium have been
modest during therapy (usually about 0.2 mmol/L), although episodes of asymptomatic
hypercalcemia increased compared to pretreatment. Mild hyperphosphatemia also
occurred, but did not appear to affect reductions in PTH. Although there are no studies
directly comparing doxercalciferol with calcitriol or alfacalcidol, it appears that
hypercalcemia and hypercalciuria may occur less frequently and be less severe with
doxercalciferol than with alfacalcidol or calcitriol. Intravenous doxercalciferol is under
investigation and data from preliminary phase III data suggest efficacy comparable to
oral administration in secondary hyperparathyroidism. Doxercalciferol also is currently
under investigation in postmenopausal osteoporosis. Trials to date suggest that the drug
produces significant and dose-related increases in serum osteocalcin, suggesting
stimulation of osteoblastic activity without altering hydroxyproline excretion (lack of
CH3 CH3
CH3 CH3

CH3

CH2

HO OH
Doxercalciferol
effect on bone resorption) and renal function. Hypercalciuria was not evident at doses
less than 5 mcg/day, but did occur at higher doses. Serum calcium increased with 4 mcg
daily only, and clinically significant hypercalcemia was not observed at any dose.

The primary adverse reactions associated with doxercalciferol therapy are hypercalcemia,
hypercalciuria, hyperphosphatemia, edema, headache, malaise. The incidence of
hypercalcemia is reported to be less than that observed for calcitriol or alfacalcidol and
usually can be controlled by dose reduction. Withdrawal of treatment due to
hypercalcemia or hypercalciuria was required only rarely in clinical trials. In several
trials, renal function, assessed by creatinine clearance and blood urea nitrogen (BUN),
was not significantly affected in patients receiving up to10 mcg of doxercalciferol.
The absorption of doxercalciferol could be reduced by cholestyramine and minerol oil
since these products are reported to interfere with the absorption of other fat soluble
vitamins. Patients receiving doxercalciferol should not use calcium, magnesium, or
phosphorus-containing drug products (antacids) or supplements. Although not
specifically studied to date, drugs that induce or inhibit hepatic enzymes have the
potential to alter the rate of doxercalciferol bioactivation and this may necessitate dosage
adjustments.

Doxercalciferol is rapidly absorbed from the GI tract and converted to the

pharmacologically active form, 1α, 25-dihydroxyvitamin D2, by hepatic cytochrome
enzymes. Another minor metabolite, 1α, 24-dihydroxyvitamin D2 also forms. Peak
blood levels of the 1α, 25-dihydroxyvitamin D2 metabolite occur at 11 to 12 hours after
repeated oral doses of 5 to 15 mcg. The active metabolite has a half-life of 32 to 37
hours. Hemodialysis causes a temporary increase in 1α,25-dihydroxyvitamin D2 mean
concentrations, probably due to volume contraction. The active metabolite is not
removed from blood during hemodialysis.

Doxercalciferol is manufactured as 2.5 microgram gelatin capsules which may be stored

at 68 to 77oF. The optimal dose of doxercalciferol must be carefully determined for each
patient. The recommended initial dose is 10 mcg administered 3 times weekly at dialysis
(approximately every other day). The initial dose may then be adjusted as needed in order
to lower blood PTH into the range of 150-300 pg/ml. The dose may be increased at 8-
week intervals by 2.5 mcg if PTH is not lowered by 50% and fails to reach the target
range. The maximum recommended dose is 20 mcg administered 3 times a week at
dialysis for a total of 60 mcg/week. The administration of doxercalciferol should be
suspended if PTH falls below 100 pg/ml. It may be restarted one week later at a dose that
is at least 2.5 mcg lower than the last administered dose. During titration, PTH, serum
calcium, and serum phosphate levels should be monitored weekly. If hypercalcemia,
hyperphosphatemia, or a serum calcium times serum phosphate product (Ca × P) > 70 is
noted, immediately suspend the drug until these parameters are appropriately lowered,
and then restart the drug at a dose that is ≤2.5 mcg. Doxercalciferol should be used with
caution in renally impaired patients, patients with renal osteodystrophy with
hyperphosphatemia (potential for metastatic calcification), pregnancy and patients using
concurrent medications that affect bone or calcium metabolism. Doxercalciferol is
contraindicated in patients with recent hypercalcemia or hyperphosphatemia, or in cases
of hypervitaminosis D.