Nephrological Department P, Rigshospitalet, University of Copenhagen, Denmark
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Abstract |
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Methods. Six healthy volunteers and 12 uraemic patients were included in the study. With an interval of 2 weeks, 4 µg of 1,25(OH)2D3 i.v., 4 µg of 1,25(OH)2D3 orally, 4 µg of 1(OH)D3 i.v. and 4 µg of 1
(OH)D3 orally were administered. Blood samples for analysis of plasma-Ca2+, plasma-1,25(OH)2D3, and plasma-PTH were drawn at time 0, 0.25, 0.5, 1, 2, 4, 6, 9, 12, 24, 48, and 72 h. The healthy volunteers were studied in all four protocols and the uraemic patients in either the 1
(OH)D3 (n=6) or the 1,25(OH)2D3 (n=6) protocol.
Results. After oral administration of 1,25(OH)2D3 the bioavailability of 1,25(OH)2D3 was 70.6±5.8/72.2±4.8% in healthy volunteers/uraemic patients (n.s.). After i.v. administration the volume of distribution of 1,25(OH)2D3 was similar, 0.49±0.14 vs 0.27±0.06 l/kg in healthy volunteers vs uraemic patients (n.s.), while the metabolic clearance rate of 1,25(OH)2D3 was 57% lower in the uraemic patients, 23.5±4.34 vs 10.1±1.35 ml/min in healthy volunteers vs uraemic patients, respectively (P<0.03). The bioavailability of 1,25(OH)2D3 after i.v. administration of 1(OH)D3 was 42.4±11.0/42.0±2.0% in healthy volunteers/uraemic patients (n.s.); and after oral administration of 1
(OH)D3 42.0±2.0/29.8±3.1% in healthy volunteers/uraemic patients (n.s.). A small, but significant increase in plasma-Ca2+ was seen after administration of 1,25(OH)2D3 to the uraemic patients, while no increase was seen after administration of 1
(OH)D3. PTH levels were significantly suppressed in the healthy volunteers 24 h after administration of 4 µg of 1,25(OH)2D3 i.v., 4 µg of 1,25(OH)2D3 orally, and 4 µg of 1
(OH)D3 orally by 35±7, 30±8, and 35±4%, respectively (all P<0.03). In the uraemic patients, PTH levels were significantly suppressed after administration of 4 µg of 1,25(OH)2D3 i.v., 4 µg of 1,25(OH)2D3 orally, and 4 µg of 1
(OH)D3 i.v. by 30±10, 45±7, and 40±7%, respectively (all P<0.04). The effect was transitory in the healthy volunteers and lasted for at least 72 h in the uraemic patients.
Conclusion. The present study found a 57% lower metabolic clearance rate of 1,25(OH)2D3 in uraemic patients, as compared with that of healthy volunteers (P<0.03). The bioavailability of 1,25(OH)2D3 following administration of 1(OH)D3 i.v. and orally in both healthy volunteers and uraemic patients was markedly lower than after administration of oral 1,25(OH)2D3 (P<0.03). In spite of lower plasma-1,25(OH)2D3 levels after administration of 1
(OH)D3, no significant difference was observed on the suppressive effect of 4 µg i.v. of either 1,25(OH)2D3 or 1
(OH)D3 on the plasma-PTH levels in the uraemic patients. This might suggest the existence of an effect of 1
(OH)D3 on the parathyroid glands which is independent of the plasma-1,25(OH)2D3 levels, that are achieved after oral or i.v. administration of 1
(OH)D3.
Keywords: calcitriol; 1-hydroxycholecalciferol; hyperparathyroidism secondary; parathyroid hormone; pharmacokinetic; uraemia
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Introduction |
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The aim of the present study therefore was (i) to evaluate the pharmacokinetics of 1,25(OH)2D3 and 1(OH)D3 in response to i.v. and oral administration in both healthy volunteers and uraemic patients and (ii) at the same time to measure the effects of a single dosethe same as aboveof the two vitamin D analogues on the plasma-PTH and plasma-Ca2+ levels in order to examine, whether possible pharmacokinetic differences would result in different biological responses.
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Subjects and methods |
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None of the healthy volunteers had been treated previously with 1,25(OH)2D3 or 1(OH)D3. One patient in the 1,25(OH)2D3 group received 1
(OH)D3 at a dose of 1 µg i.v. once a week until 1 week before the study. In the 1
(OH)D3 group one patient received 1
(OH)D3 orally at a dose of 1 µg every second day until 3 months before, one patient 0.5 µg orally once daily until 6 weeks before, and one patient 1 µg once a day until 1 week before the study. No active vitamin D analogues were administered between the two study periods. Further, the patients in the 1,25(OH)2D3/1
(OH)D3 group were treated with: prednisolone 0/1, isosorbidnitrat 0/1, digoxin 0/3, Ca-channel blockers 4/2, pinacidil 1/0, metoprolol 2/0, furosemid 1/5, potassium 0/1, acetylsalicylic acid 0/1, terfenadin 1/0, cyproheptadin 0/1, quinin 1/0, warfarin 1/1, anxiolytika 0/4, insulin 0/1, cephalexin 0/1, netilmicin 0/1, ferro 2/0, erythropoietin 6/0, omeprazol 3/0, cimetidin 0/4, and phenytoin 0/1. All patients gave their informed consent to participate in the study, which was approved by the Danish Ethical Committee for Medical Research.
Treatment schedule
Healthy volunteers
Initially an indwelling i.v. catheter was placed in both cubital veins: one for administration of 1(OH)D3 or 1,25(OH)2D3 and the other for blood sampling. Two sets of blood samples were obtained initially as basal values. Then at time zero, 4 µg of 1,25(OH)2D3 (Calcijex®, Abbott) was injected as a bolus. Blood samples for analysis of plasma-Ca2+, plasma-1,25(OH)2D3 and plasma-PTH were drawn at time 0, 0.25, 0.5, 1, 2, 4, 6, 9, 12, 24, 48, and 72 h. With an interval of 2 weeks, the same schedule was performed in the same healthy volunteer, but with administration of 4 µg of 1,25(OH)2D3 orally (Rocaltrol®, Roche), 4 µg of 1
(OH)D3 intravenously (Etalpha®, Leo, Denmark) and 4 µg of 1
(OH)D3 orally (Etalpha®), respectively. This means that the single healthy volunteer was studied in all four protocols.
Uraemic patients
Because of the need to obtain 10 ml of blood for each analysis of 1,25(OH)2D3 the uraemic patients had to be divided into two groupsone group that had 4 µg of 1(OH)D3 orally and then intravenously or vice versa (the 1
(OH)D3 group, n=6) and another group that had 4 µg of 1,25(OH)2D3 orally and then intravenously or vice versa (the 1,25(OH)2D3 group, n=6).
Exactly the same schedule as described for the healthy volunteers was then performed with administration of 4 µg of 1(OH)D3 intravenously and orally (Etalpha®) for the 1
(OH)D3 group and 4 µg of 1,25(OH)2D3 intravenously (Calcijex®) and orally (Rocaltrol®) for the 1,25(OH)2D3-group.
The producers of the different vitamin D analogues have reported that the variation between the designated and the actually delivered dose for inj. Calcijex® (Abbott) was 90125%, 95115% for caps. Rocaltrol®, 95105% for inj. Etalpha®, and 90115% for caps. Etalpha®.
At the beginning of each session, blood samples were analysed for total plasma-calcium, plasma-inorganic phosphate (Pi), plasma-alkaline phosphatases, plasma-alanine aminotransferase (ALAT), plasma-lactate dehydrogenase (LDH), plasma-coagulation factor II, VII, X (PP), and plasma-albumin and after 72 h again also for total plasma-calcium and plasma-Pi.
Methods
The 1,25(OH)2D3 was extracted from plasma with diethyl ether, and extracts were chromatographed. 1,25(OH)2D3 was measured by a competitive protein binding assay using calf thymus cytosol as the source of binding protein. The sensitivity is 3 pg/ml, the intra-assay variation 3.8% and the inter-assay variation 14.7%. In our laboratory the normal range is 37.7±11.2 pg/ml (±SD).
Plasma-PTH 1-84 was measured by an immunoradiometric assay (IRMA, Allegro, from Nichols Institute, USA). The sensitivity is 1 pg/ml, the intra-assay variation is 3%, and the inter-assay variation 6%. The normal range in our laboratory is 1055 pg/ml, determined in 255 normal subjects.
Plasma-Ca2+ and pH were measured by a calcium ion electrode analyser (ICA 2, Radiometer, Copenhagen, Denmark). Total plasma-calcium and plasma-inorganic Pi were measured by photometry. Plasma-alkaline phosphatase, plasma-ALAT, plasma-LDH, plasma-PP, and plasma-albumin were measured by standard laboratory tests. Blood samples for determination of plasma-Ca2+ and pH were measured immediately. Blood samples for the determination of plasma-1,25(OH)2D3 and plasma-PTH were immediately placed on ice, centrifuged at 4°C, and stored at -20°C until analysis.
Calculations
Calculation of the pharmacokinetics was performed in the following way. After i.v. administration of 1,25(OH)2D3 the concentration vs time curves exhibited a biexponential decline on a semi-logarithmic plot with an initial more rapid distribution phase () and a terminal elimination phase (ß). By extrapolating the exponential curves to time zero, corresponding to the two compartment model, the initial concentrations of 1,25(OH)2D3, corresponding to the phases of C
0 and Cß0 were determined. The theoretical maximal 1,25(OH)2D3 concentration was then calculated as C0=C
0+Cß0 and the initial volume of distribution (Vd initial) of 1,25(OH)2D3 as the test dose/C0. The AUC after i.v. as well as oral dosages (AUCi.v. and AUCp.o.) was calculated by trapezoidal integration from zero to 72 h. The bioavailability of 1,25(OH)2D3 after 1,25(OH)2D3 orally was then determined as F=AUCp.o./AUCi.v. and the bioavailability of 1,25(OH)2D3 after oral and i.v. administration of 1
(OH)D3 as the respective AUCs divided by AUC1,25 i.v.. In uraemia, where the uraemic patients who received 1
(OH)D3 and 1,25(OH)2D3 were different subjects, the bioavailability of 1,25(OH)2D3 after oral and i.v. administration of 1
(OH)D3 was calculated as the respective AUCs divided by mean AUC1,25 i.v. obtained in uraemic patients. The clearance (Cl) of 1,25(OH)2D3 was calculated as Cl=test dose/AUC(1,25 i.v.). The final volume (Vd) of distribution of 1,25(OH)2D3 at steady state was calculated as Cl/-k, where k was the elimination rate constant of the ß-phase of the 1,25(OH)2D3 disappearance curve after i.v. administration. The terminal elimination half-life (t1/2) of 1,25(OH)2D3 was calculated as (t1/2)=ln2/-k, where ln2 was the natural logarithm of 2 [11]. Maximal increase in plasma-1,25(OH)2D3 level (
-maximum plasma-level), time to reach maximal plasma-1,25(OH)2D3 level and time to decrease maximal plasma-1,25(OH)2D3 level by 50% (T50% maximum plasma-level) were calculated as mean±SEM of the results obtained in the single subject.
Statistics
For comparison of mean values during the different study periods, two-way analysis of variance, as described by Altman [12] was used. Guided by these results a paired/unpaired Student's t-test was used for comparison of mean values between specific time periods. A P value <0.05 was considered statistically significant.
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Results |
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Pharmacokinetics of 1,25(OH)2D3 after 1,25(OH)2D3 or 1(OH)D3 administration to healthy volunteers
The plasma-1,25(OH)2D3 concentrations vs time after i.v. and oral administration of 4 µg of 1,25(OH)2D3 and 4 µg of 1(OH)D3 are summarized in Figure 1
. A semi-logarithmic transformation of the plasma-1,25(OH)2D3 i.v. course is inserted in Figure 1
.
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1(OH)D3 given orally resulted in a maximal increase of the plasma-1,25(OH)2D3 concentrations of 70.9±23.4 pg/ml (Table 2
) reached after 6.5±1.5 h. A decline in plasma-1,25(OH)2D3 to levels not significantly different from baseline levels was achieved after 24 h (Figure 1
). The bioavailability of 1,25(OH)2D3 after oral administration of 1
(OH)D3 was 43.8±9.2% (Table 4
). t1/2 of 1,25(OH)2D3 was 47.1±4.0 h. The time to reduce maximal plasma-1,25(OH)2D3 concentration by 50% was 37.7±9.0 h (Table 2
). The results obtained after oral administration of 1
(OH)D3 were very similar to and not significantly different from the results obtained after i.v. 1
(OH)D3 administration.
Pharmacokinetics of 1,25(OH)2D3 after 1,25(OH)2D3 or 1(OH)D3 administration to chronically uraemic patients
The plasma-1,25(OH)2D3 concentrations vs time after i.v. and oral administration of 4 µg of 1,25(OH)2D3 and 4 µg of 1(OH)D3 are summarized in Figure 2
. A semi-logarithmic transformation of the plasma-1,25(OH)2D3 i.v. course is inserted in Figure 2
.
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1(OH)D3 given i.v. resulted in a maximal increase of plasma-1,25(OH)2D3 of 147.0±17 pg/ml after 3.5±0.6 h, significantly higher than observed in healthy volunteers (P<0.005) (Table 2,
Figure 3
). Plasma-1,25(OH)2D3 declined to levels not significantly different from baseline levels after 72 h (Figure 2
). The bioavailability of 1,25(OH)2D3 was 42.0±2.0% (Table 4
), not different from healthy volunteers, but significantly lower than following administration of 1,25(OH)2D3 (P<0.03). t1/2 of 1,25(OH)2D3 was 36.7±6.7 h (Table 2
) not significantly different from healthy volunteers. The time to reduce the maximal plasma-1,25(OH)2D3 concentration by 50% was 14.3±3.5 h, which was significantly faster than after oral administration (P<0.01) and significantly faster than in healthy volunteers (P<0.03) (Table 2
).
1(OH)D3 given orally resulted in a maximal increase of plasma-1,25(OH)2D3 concentrations of 73.0±12.5 pg/ml after 7.6±1.4 h (Table 2
) a concentration vs time curve similar to that of healthy volunteers (Table 3
). The peak levels were significantly lower than after i.v. administration (P<0.005) (Tables 2
and 3
). Plasma-1,25(OH)2D3 declined to levels not significantly different from baseline levels after 48 h (Figure 2
). The bioavailability was 29.7±3.1% (Table 4
), not significantly different from that of healthy volunteers. t1/2 of 1,25(OH)2D3 was 29.2±5.2 h (Table 2
), and the time to reduce maximal plasma-1,25(OH)2D3 by 50% was 32.1±5.6 hnot significantly different from that of healthy volunteers.
PTH
The baseline PTH levels in the healthy volunteers were within the normal range (23.5±0.33 pg/ml, Table 1), and moderately elevated in the uraemic patients (P<0.006) (1,25(OH)2D3 group 137.3±33 pg/ml, 1
(OH)D3 group 173.3±84 pg/ml, Table 1
), with no significant difference between the two uraemic groups.
The baseline PTH levels, which were obtained at the beginning of each of the four different protocols in the healthy volunteers and in each of the two different protocols in the 1(OH)D3 and 1,25(OH)2D3 group, were not significantly different from each other. The baseline PTH values are therefore presented as the mean PTH values obtained at the beginning of each study (Table 1
). The changes in PTH after administration of 4 µg of each of the two vitamin D metabolites are presented as per cent of baseline PTH levels (Figure 4
). In the healthy volunteers, PTH levels were significantly lower than baseline levels 24 h after administration of 4 µg of 1,25(OH)2D3 i.v. (P<0.004), after oral administration of 1,25(OH)2D3 at 9, 12, and 24 h (P<0.05, P<0.03, and P<0.03) and after oral administration of 1
(OH)D3 at 24 h (P<0.0005) (Figure 4
). 1
(OH)D3 i.v. had no suppressive effect on plasma-PTH levels within 24 h.
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Using two-way analysis of variance, no significant changes in plasma-PTH levels were observed in healthy volunteers after administration of 4 µg of 1(OH)D3 i.v. and in uraemic patients after administration of 4 µg of 1
(OH)D3 orally within the 72 h. When the suppression of plasma-PTH was compared after administration of 1,25(OH)2D3 and 1
(OH)D3 orally in healthy volunteers and after administration of 1,25(OH)2D3 and 1
(OH)D3 i.v. in uraemic patients, no significant differences were observed (Figure 4
).
Plasma-Ca2+
Plasma-Ca2+ was initially within normal limits in both healthy volunteers and uraemic patients (Table 1). No significant changes were seen in the healthy volunteers while a small, but significant increase of plasma-Ca2+ was observed in the uraemic group 48 and 72 h after administration of 1,25(OH)2D3 i.v. (P<0.02 and P<0.02) and 12, 24, and 48 h after administration of 1,25(OH)2D3 orally (P<0.02, P<0.007, and P<0.02) (Figure 4
).
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Discussion |
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The clearance of 1,25(OH)2D3 was calculated as test dose/AUC(1,25 i.v.). The AUC1,25 of both oral and i.v. administration was significantly higher in uraemic patients than in healthy volunteers (P<0.004). This is in accordance with the results of the literature, as stated in Tables 5 and 7
. In a single study on uraemic patients, no difference in AUC between oral and i.v. administration of 2 µg of 1,25(OH)2D3 was found [15]. The Vd initial (initial volume of distribution) and final Vd (volume of distribution) of 1,25(OH)2D3 were the same in healthy volunteers and uraemic patients. Final Vd was higher than the Vd initial demonstrating the well known affinity of vitamin D binding globulin for 1,25(OH)2D3.
The maximal plasma-1,25(OH)2D3 levels after oral administration of 1,25(OH)2D3 were significantly lower (P<0.02) than after i.v. administration of 1,25(OH)2D3 to both healthy volunteers and uraemic patients, similar to the calculated AUC levels, reflecting an oral bioavailability of about 70%. This could be explained by incomplete absorption, local intestinal degradation, and/or hepatic metabolism of enterally absorbed 1,25(OH)2D3 (first pass effect).
A comparison of 1(OH)D3 given orally and intravenously to the same healthy volunteer has to our knowledge not been reported previously, and only reported once in uraemic patients [16]. The plasma levels of 1,25(OH)2D3 obtained after either i.v. or oral administration of 1
(OH)D3 were significantly different in the uraemic patients (P<0.03) with the highest plasma peak level obtained after i.v. administration. In the healthy volunteers the plasma levels of 1,25(OH)2D3 after i.v. and oral administration of 1
(OH)D3 were similar and not different from the results obtained after oral administration of 1
(OH)D3 to uraemic patients. The reason for this unexpected dissimilarity between the metabolism of 1
(OH)D3 after i.v. administration to uraemic patients and healthy volunteers is unclear. It is, at the present time, not possible to measure plasma-concentration of 1
(OH)D3 without administration of radioactive labelled 1
(OH)D3. In this study the commercially available drug was used and, therefore, it was not possible to calculate the terminal elimination half-life (t1/2) for 1
(OH)D3. The time involved before the maximal plasma levels of 1,25(OH)2D3 were reduced by 50% (T50% maximum plasma level) was nearly two times longer after oral and i.v. administration of 1
(OH)D3 than after similar administration of 1,25(OH)2D3 to healthy volunteers (P<0.02). The continuous conversion of 1
(OH)D3 to 1,25(OH)2D3 is presumably a contributory factor to the longer T50% maximum plasma level after administration of 1
(OH)D3.
The bioavailability of 1,25(OH)2D3 after administration of 1(OH)D3 was only 40% in both normal and uraemic subjects (Table 4
). The peak levels achieved after oral and i.v. administration of 1
(OH)D3 were in the present study as described in other studies [46] only about 50% of the plasma levels achieved after similar doses of 1,25(OH)2D3 (Table 7
). The exact reason for this is not known, but might be due to metabolism of 1
(OH)D3 to substances other than 1,25(OH)2D3 [17], due to excretion of non-metabolized 1
(OH)D3, or due to deposition of 1
(OH)D3. Against these possibilities are, however, that the fecal radioactivity of 1
(OH)D3 after i.v. administration of 3H-1
(OH)D3 has been found to be only 5% [17], and the rapid rate of reversal of plasma-calcium and calcium excretion after stop of treatment [18].
The terminal elimination half-life (t1/2) of 1,25(OH)2D3 after administration of 1(OH)D3 was in the present, as in other studies [4,16], based upon the elimination rate constant of the ß-phase of the 1,25(OH)2D3 disappearance curve. In the present study on healthy volunteers, t1/2 of 1,25(OH)2D3 was significantly longer after oral and i.v. administration of 1
(OH)D3 than after oral and i.v. administration of 1,25(OH)2D3 (P<0.02).
In the uraemic patients, t1/2 of 1,25(OH)2D3 was not significantly different between 1(OH)D3 and 1,25(OH)2D3, independent of the form of administration in contrast to what has been found in another investigation [4]. Neither in the healthy volunteers nor in the uraemic patients of the present study were significant differences in t1/2 of 1,25(OH)2D3 found between oral and i.v. administration of 1
(OH)D3.
Only a few studies have measured the plasma-levels of 1,25(OH)2D3, which were generated after administration to the same subject of either 1,25(OH)2D3 or 1(OH)D3 (Table 7
). In the present study, the same dose of 1,25(OH)2D3 and 1
(OH)D3 was administered to the same healthy volunteer, resulting in significantly higher peak levels of 1,25(OH)2D3 (P<0.009) and significantly greater AUC (P<0.02) after administration of 1,25(OH)2D3 than after similar administration of 1
(OH)D3. The time to reach peak levels of 1,25(OH)2D3 in healthy volunteers and uraemic patients was significantly shorter after oral administration of 1,25(OH)2D3 than after oral administration of 1
(OH)D3 (healthy volunteers: 2.3±0.4 vs 6.5±1.5, P<0.05; uraemic patients: 3.5±1.2 vs 7.6±1.4 h, P<0.05), presumably reflecting the time used to convert 1
(OH)D3 to 1,25(OH)2D3. The results obtained in the present study are, however, generally in accordance with the scattered previously reported results, as indicated in Table 7
.
The acute effect of a single dose of 1,25(OH)2D3 compared with 1(OH)D3 on the suppression of PTH secretion in healthy volunteers has only sporadically been studiedand to our best knowledge not in a direct comparative set-up as in the present study. In healthy volunteers the results of previous investigations did not demonstrate any acute suppressive effect on PTH secretion for up to 12 h of 1,25(OH)2D3 i.v. [19], 1,25(OH)2D3 orally [20], or 1
(OH)D3 i.v. [21] at doses from 1.5 to 2.7 µg.
In chronically uraemic children with persistent HPT a suppression of PTH levels 12 h after administration of a single dose of 1.5 µg/m2 of 1,25(OH)2D3 orally and i.v. [22] has been demonstrated previously. The same was found in patients on CAPD with persistent HPT after a single dose of 80 ng/kg of 1(OH)D3 orally or i.v. [23]. In patients on chronic haemodialysis with persistent HPT, several studies have demonstrated a direct suppressive effect on PTH secretion after intermittent administration two to three times a week of 1,25(OH)2D3 or 1
(OH)D3 [1,2,9]. One study demonstrated a suppression of PTH secretion 48 h after administration of a single dose of 8 µg of 1,25(OH)2D3 i.v. [24], while another study did not observe any effect for 44 h after administration of a single dose of 4 µg of 1
(OH)D3 [8]. Neither 4 µg of 1,25(OH)2D3 or of 1
(OH)D3 given i.v. as a single shot immediately before dialysis caused any suppression of plasma-PTH during dialysis [25]. The present study found in healthy volunteers a transitory suppressive effect on plasma-PTH levels 1224 h after 4 µg of oral 1
(OH)D3 and 1224 h after oral as well as i.v. 1,25(OH)2D3. In uraemic patients a similar significant suppression of plasma-PTH levels of i.v. 1
(OH)D3 and of i.v. as well as oral 1,25(OH)2D3 was observed, which lasted for at least 72 h. This suppressive effect in uraemic patients of i.v. 1
(OH)D3 and 1,25(OH)2D3 on the plasma-PTH levels was not significantly different. This is in accordance with the clinical experience that 1
(OH)D3 and 1,25(OH)2D3 are both effective drugs in the treatment of sec. HPT [13]. Presumably, due to the small number of patients included, no suppressive effect on plasma-PTH levels was observed after administration of 1
(OH)D3 i.v. to healthy volunteers and of 1
(OH)D3 orally to uraemic patients. The concomitantly small, but significant increase in plasma-Ca2+ observed in the uraemic patients after administration of 1,25(OH)2D3 does however not allow for any specific conclusions to be made on the exact therapeutic equivalence of the two drugs.
As the peak concentration of 1,25(OH)2D3 after administration of 1(OH)D3 was markedly lower than that obtained after similar doses of 1,25(OH)2D3, either the peak concentration of 1,25(OH)2D3 is probably of less importance for the direct suppression of PTH secretion than assumed previously, or the effect of 1
(OH)D3 on the PTH secretion in uraemic patients cannot alone be explained by the conversion of 1
(OH)D3 to 1,25(OH)2D3. Therefore, the theoretical possibility exists that the 25-hydroxyl group might not be mandatory for the activity of vitamin D3 in the parathyroid glands, but that the 1
-hydroxyl group is the structural feature required for the expression of the hormonal activity on PTH gene suppression. This assumption is supported by results from an in vitro study from our laboratory where the suppression of PTH secretion from bovine parathyroid cells by 1
(OH)D3 was equal to that of 1,25(OH)2D3 [26].
In conclusion, the present study demonstrated a 57% lower metabolic clearance rate of 1,25(OH)2D3 in uraemic patients, as compared with healthy volunteers (P<0.03). The bioavailability of 1,25(OH)2D3 following administration of 1(OH)D3 i.v. and orally to both healthy volunteers and uraemic patients was markedly lower than after administration of oral 1,25(OH)2D3 (P<0.03). In spite of lower plasma-1,25(OH)2D3 levels after administration of 1
(OH)D3, no significant difference was observed on the suppressive effect of 4 µg intravenously of either 1,25(OH)2D3 or 1
(OH)D3 on the plasma-PTH levels in the uraemic patients. This might suggest the existence of an effect of 1
(OH)D3 on the parathyroid glands which is independent of the plasma-1,25(OH)2D3 levels, that are achieved after oral or i.v. administration of 1
(OH)D3.
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Acknowledgments |
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Notes |
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References |
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