Page 790 - Basic _ Clinical Pharmacology ( PDFDrive )

776 SECTION VII Endocrine Drugs

22 26
21
20 23 24 25
18 27
19 12 17
11 13 16
CH 3 14 15 CH 3
1 9 1
2 10 8 Ultraviolet 2 10 Heat
3 4 5 6 7 3 5
HO HO 4
CH 2
7-Dehydrocholesterol Pre D 3 D 3 (cholecalciferol)
HO
O
H O
H

+ P + Ca
+ 1,25(OH) 2 D
− PTH
O + FGF23 CH 2
H
HO
Liver Kidney
24,25 (OH) 2 D 3 (secalciferol)
CH 2
− P − Ca
HO CH 2 + PTH
− FGF23
D 3
HO O
H
25 (OH)D 3
28
CH 3

22 26 CH 2
21
24
20 23 25 HO OH
27
1,25 (OH) 2 D 3 (calcitriol)

FIGURE 42–3 Conversion of 7-dehydrocholesterol to vitamin D 3 in the skin and its subsequent metabolism to 25-hydroxyvitamin D 3
(25[OH]D 3 ) in the liver and to 1,25-dihydroxyvitamin D 3 (1,25[OH] 2 D 3 ) and 24,25-dihydroxyvitamin D 3 (24,25[OH] 2 D 3 ) in the kidney. Control of
vitamin D metabolism is exerted primarily at the level of the kidney, where high concentrations of serum phosphorus (P) and calcium (Ca) as
well as fibroblast growth factor 23 (FGF23) inhibit production of 1,25(OH) 2 D 3 (indicated by a minus [−] sign), but promote that of 24,25(OH) 2 D 3
(indicated by a plus [+] sign). Parathyroid hormone (PTH), on the other hand, stimulates 1,25(OH) 2 D 3 production but inhibits 24,25(OH) 2 D 3
production. The insert (shaded) shows the side chain for ergosterol, vitamin D 2 , and the active vitamin D 2 metabolites. Ergosterol is converted to
vitamin D 2 (ergocalciferol) by UV radiation similar to the conversion of 7-dehydrocholesterol to vitamin D 3 . Vitamin D 2 , in turn, is metabolized to
25-hydroxyvitamin D 2 , 1,25-dihydroxyvitamin D 2 , and 24,25-dihydroxyvitamin D 2 via the same enzymes that metabolize vitamin D 3 . In humans,
corresponding D 2 and D 3 metabolites have equivalent biologic effects, although they differ in pharmacokinetics. +, facilitation; –, inhibition; P,
phosphorus; Ca, calcium; PTH, parathyroid hormone; FGF23, fibroblast growth factor 23.

of DBP in the population with different affinities for the vitamin a rapid turnover, with a terminal half-life measured in hours.
D metabolites, and, as noted earlier, the affinity of DBP for the Several of the 1,25(OH) D analogs are bound poorly by DBP.
2
D metabolites is less than that for the D metabolites. Thus As a result, their clearance is very rapid, with a terminal half-life
2
3
individuals can vary with respect to the fraction of free metabolite of minutes. Such analogs have less hypercalcemic, hypercalciuric
available, so that measuring only the total metabolite concentra- effects than calcitriol, an important aspect of their use in the man-
tion may be misleading with respect to assessing vitamin D status. agement of conditions such as psoriasis and hyperparathyroidism.
In normal subjects, the terminal half-life of injected calcifediol The mechanism of action of the vitamin D metabolites
(25[OH]D) is around 23 days, whereas in anephric subjects it is remains under active investigation. However, 1,25(OH) D is well
2
around 42 days. The half-life of 24,25(OH) D is probably similar. established as the most potent stimulant of intestinal calcium
2
Tracer studies with vitamin D have shown a rapid clearance from and phosphate transport and bone resorption. 1,25(OH) 2 D
the blood. The liver appears to be the principal organ for clear- appears to act on the intestine both by induction of new protein
ance. Excess vitamin D is stored in adipose tissue. The metabolic synthesis (eg, calcium-binding protein and TRPV6, an intestinal
D) in humans likewise indicates calcium channel) and by modulation of calcium flux across the
clearance of calcitriol (1,25[OH] 2