Effect of vitamin D3 supplementation on the pharmacokinetics of digoxin - a pilot study

Faculty of Pharmacy, University of Sydney, Camperdown, NSW 2006, Australia.
Fundamental and Clinical Pharmacology (Impact Factor: 2.12). 04/2011; 26(4):543-8. DOI: 10.1111/j.1472-8206.2011.00944.x
Source: PubMed


Emerging evidence from preclinical, clinical and epidemiological studies suggests that vitamin D3 plays vital roles in several diseases in addition to bone disorders. According to new medical evidence, it is being recommended that vitamin D3 intake to be increased for maximal benefits in human health. However, it is necessary to consider potential side effects of increased intake of vitamin D3. Vitamin D3 exerts its actions through the vitamin D receptor, which is known to be an important regulator of P-glycoprotein (P-gp). As P-gp plays a significant role in limiting drug bioavailability, we undertook a study to compare single-dose digoxin (a P-gp substrate) pharmacokinetics in eight healthy male subjects before and after vitamin D3 supplementation (1000 IU per day). The geometric mean ratios for AUC(0-3h), AUC(0-48h) and C(max) were 1.06 (90% CI 0.92, 1.21) and 1.02 (90% CI 0.97, 1.08) and 1.03 (95% CI 0.86, 1.24), respectively. The median for digoxin T(max) was 0.75 h before and after vitamin D3 ingestion. The mean plasma 25-hydroxyvitamin D3 (25(OH)D3) levels remained constant after the intake of vitamin D3 (15.4 ± 3.7 and 14.4 ± 3.6 ng/mL, respectively), while there was a modest but statistically significant increase in plasma calcium levels, from 9.32-9.68 mg/dL (P = 0.0277). These results suggest that vitamin D3 supplementation (1000 IU per day) in human volunteers does not produce a P-gp-mediated drug interaction with orally administered digoxin.

10 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to determine vitamin D supplementation effects on concentrations of atorvastatin and cholesterol in patients. Sixteen patients (8 men, 8 women; 10 Caucasians, 4 African Americans, 1 Hispanic, 1 Asian), aged 63 +/- 11 years (mean +/- SD, weight 92 +/- 31 kg) on atorvastatin (45 +/- 33 mg/day) were studied with and without supplemental vitamin D (800 IU/day for 6 weeks). Levels of vitamin D (1,25-dihydroxy(OH) and 25 OH-metabolites), atorvastatin (parent, OH-acid metabolites, lactone, and lactone metabolites), and cholesterol (total, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol) were determined at 0.5, 3, and 10 h after dosing. Vitamin D supplementation increased vitamin D-25-OH metabolites (P < 0.0001) without increased 1,25-dihydroxy vitamin D. Atorvastatin and active metabolite concentrations (P < 0.001) as well as LDL-cholesterol and total-cholesterol levels (97 +/- 28 mg/dl vs. 83 +/- 30 and 169 +/- 35 mg/dl vs. 157 +/- 37, P < 0.005) were lower during vitamin D supplementation. The conclusion of the study is that vitamin D supplementation lowers atorvastatin and active metabolite concentrations yet has synergistic effects on cholesterol concentrations.
    Clinical Pharmacology &#38 Therapeutics 09/2008; 85(2):198-203. DOI:10.1038/clpt.2008.165 · 7.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 1alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the natural ligand of the vitamin D receptor (VDR), was found to regulate bile acid related transporters and enzymes directly and indirectly in the rat intestine and liver in vivo. The kidney is another VDR-rich target organ in which VDR regulation on xenobiotic transporters and enzymes is ill-defined. Hence, changes in protein and mRNA expression of nuclear receptors, transporters and enzymes of the rat intestine and kidney in response to 1,25(OH)2D3 treatment (0 to 2.56 nmol/kg/day intraperitoneally in corn oil for 4 days) were studied. In the intestine, protein and not mRNA levels of Mrp2, Mrp3, Mrp4 and PepT1 in the duodenum and proximal jejunum were induced, whereas Oat1 and Oat3 mRNA were decreased in the ileum after 1,25(OH)2D3 treatment. In the kidney, VDR, Cyp24, Asbt and Mdr1a mRNA and protein expression increased significantly (2- to 20-fold) in 1,25(OH)2D3-treated rats, and a 28-fold increase of Cyp3a9 mRNA but not of total Cy3a protein nor Cyp3a1 and Cyp3a2 mRNA was observed, implicating that VDR played a significant, renal-specific role in Cyp3a9 induction. Additionally, renal mRNA levels of PepT1, Oat1, Oat3, Ostalpha, and Mrp4, and protein levels of PepT1 and Oat1 were decreased in a dose-dependent manner, and the approximately 50% concomitant reduction in FXR, SHP, HNF-1alpha and HNF-4alpha mRNA expression suggests the possibility of cross-talk among the nuclear receptors. It is concluded that the effects of 1,25(OH)2D3 changes are tissue-specific, differing between the intestine and kidney which are VDR-rich organs.
    Biopharmaceutics & Drug Disposition 01/2009; 31(1):91-108. DOI:10.1002/bdd.694 · 2.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: P-glycoprotein, encoded by the multidrug resistance 1 (MDR1) gene, is an efflux transporter and plays an important role in pharmacokinetics. The expression of MDR1 is induced by a variety of compounds, of which 1alpha,25-dihydroxyvitamin D(3) is known to be an effective inducer. However, it remains unclear how 1alpha,25-dihydroxyvitamin D(3) regulates the expression of MDR1. In this study, we demonstrated that the vitamin D receptor (VDR) induces MDR1 expression in a 1alpha,25-dihydroxyvitamin D(3)-dependent manner. Luciferase assays revealed that the region between -7.9 and -7.8k bp upstream from the transcription start site of the MDR1 is responsible for the induction by 1alpha,25-dihydroxyvitamin D(3). Electrophoretic mobility shift assays revealed that several binding sites for the VDR/retinoid X receptor alpha (RXRalpha) heterodimer are located between the -7880 and -7810 bp region, to which the three molecules of VDR/RXRalpha are able to simultaneously bind with different affinities. Luciferase assays using mutated constructs revealed that the VDR-binding sites of DR3, DR4(I), MdC3, and DR4(III) contribute to the induction, indicating that these binding sites act as vitamin D response elements (VDREs). The contribution of each VDRE to the inducibility was different for each response element. An additive effect of the individual VDREs on induced luciferase activity by 1alpha,25-dihydroxyvitamin D(3) was also observed. These results indicate that the induction of MDR1 by 1alpha,25-dihydroxyvitamin D(3) is mediated by VDR/RXRalpha binding to several VDREs located between -7880 and -7810bp, in which every VDRE additively contributes to the 1alpha,25-dihydroxyvitamin D(3) response.
    Biochemical pharmacology 08/2008; 76(4):531-42. DOI:10.1016/j.bcp.2008.05.030 · 5.01 Impact Factor
Show more