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Figure 3-1) (Jones et al., 1998). The enzyme CYP24A1 is found in all target tissues and is induced in response to calcitriol interacting with the VDR. CYP24A1 is largely responsible for the metabolic degradation of calcitriol and its precursor, 25OHD, and its deletion in the mouse results in 50 percent lethality at weaning and an inability to efficiently clear the active form of vitamin D (Masuda et al., 2005). CYP24A1 carries out a series of reactions resulting ultimately in production of calcitroic acid from calcitriol and 1-desoxycalcitroic acid from 24,25(OH)2D, the major metabolite of 25OHD. These products are excreted through the bile into the feces (Jones et al., 1998); very little is eliminated through the urine (Kumar et al., 1976). The active forms of vitamin D2 are also catabolized by CYP24A1 into a series of biliary metabolites, somewhat analogous to those of vitamin D3.

As described above, all naturally occurring vitamin D compounds interact with DBP. Calcitriol and vitamin D have significantly lower affinity for this protein than does 25OHD. Whereas vitamin D has an average lifetime in the body of approximately 2 months, 25OHD has a lifetime of 15 days, and calcitriol has a lifetime measured in hours (Jones et al., 1998). Aside from these key elements in vitamin D metabolism, more than 30 other metabolites have been found, including the 3-epi series of vitamin D compounds (DeLuca and Schnoes, 1983; Siu-Caldera et al., 1999). Their importance seems minimal and need not be discussed here.

Although the route of catabolism between 1α,25(OH)2D2 and 1α,25(OH)2D3 differs beyond the initial 24-hydroxylation step, because 24-hydroxylation is primarily a deactivation step (Brommage and DeLuca, 1985; Horst et al., 1986; Lohnes and Jones, 1992; Jones et al., 1998), the rate of this initial step should be the important indicator of the loss of biological action. Comparisons of initial rate kinetics of the 24-hydroxylase enzyme (CYP24A1) activity toward 1α,25(OH)2D2 and 1α,25(OH)2D3 and their precursors suggest that the rates of inactivation by CYP24A1 in vitro are virtually identical (Jones et al., 2009; Urushino et al., 2009). Although side-chain hydroxylation of 1α,25(OH)2D2 represents the primary route of metabolism in the target cell, clearance of the metabolic products in vivo is complicated by additional non-specific liver CYPs (e.g., CYP3A4) (Gupta et al., 2004, 2005) that are inducible by 1α,25(OH)2D3 in certain extra-hepatic tissues (Thompson et al., 2002) and also Phase II enzymes, including uridine diphosphate–glucuronosyl transferases, which are known to subject vitamin D metabolites to glucuronidation (LeVan et al., 1981; Hashizume et al., 2008). The pharmacokinetic consequence of the sum of these catabolic systems, as shown in studies in rats, is a slightly reduced half-life for 1α,25(OH)2D2 compared with 1α,25(OH)2D3 (Knutson et al., 1997).

There are reports that vitamin D2 and vitamin D3 are differentially susceptible to these non-specific inactivating modifications, such as those occurring in the liver in response to a variety of drugs. These enzymes in-

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