Therapeutic targets of vitamin D receptor ligands and their pharmacokinetic effects by modulation of transporters and metabolic enzymes
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Vitamin D is involved in retaining the balance of several minerals in the body, such as calcium and phosphate, which are crucial for the bone formation and development. These physiological effects of vitamin D are mediated by activation of the transcription factor vitamin D receptor (VDR). Moreover, vitamin D is closely related to several pathological conditions including osteoporosis, secondary hyperparathyroidism, cancer, psoriasis and autoimmune diseases, which is not only due to calcemic but also non-calcemic effects of vitamin D such as cell proliferation, differentiation, and immunomodulation. These various abilities of vitamin D have made VDR an attractive therapeutic target. Already, numerous vitamin D analogs have been developed and studied in in vitro disease models or animal models, and some have been in clinical trials or approved for the treatment of certain diseases. In addition, the transcriptional and/or post-transcriptional regulation by VDR activation also affects the genes involved in drug metabolism and disposition, possibly leading to pharmacokinetic changes of several drugs in clinical use. This review provides a detailed summary of therapeutic targets of VDR ligands, and their effects on the transporters and metabolic enzymes, causing in vitro and in vivo pharmacokinetic changes of several drugs. The clinical research is further required for the confirming the clinical relevance of pharmacokinetic drug interactions by VDR ligands.
KeywordsVitamin D Vitamin D receptor (VDR) Therapeutic target Transporters Metabolic enzymes Pharmacokinetics
This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2016R1D1A1B03931470).
Compliance with ethical standards
Conflict of the interest
These authors declare that they have no conflict of interest.
Human and animal rights participants
All institutional and national guidelines for the care and use of laboratory animals were followed.
- Aguilera O, Peña C, García JM, Larriba MJ, Ordóñez-Morán P, Navarro D, Barbáchano A, López de Silanes I, Ballestar E, Fraga MF, Esteller M, Gamallo C, Bonilla F, González-Sancho JM, Muñoz A (2007) The Wnt antagonist DICKKOPF-1 gene is induced by 1α,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells. Carcinogenesis 28:1877–1884CrossRefPubMedGoogle Scholar
- Akizawa T, Suzuki M, Akiba T, Nishizawa Y, Ohashi Y, Ogata E, Slatopolsky E, Kurokawa K (2002) Long-term effect of 1,25-dihydroxy-22-oxavitamin D(3) on secondary hyperparathyroidism in haemodialysis patients. One-year administration study. Nephrol Dial Transplant 17(Suppl. 10):28–36CrossRefPubMedGoogle Scholar
- Brown AJ, Finch JL, Lopez-Hilker S, Dusso A, Ritter C, Pernalete N, Slatopolsky E (1990) New active analogues of vitamin D with low calcemic activity. Kidney Int 29(Suppl. 29):S22–S27Google Scholar
- Chen X, Chen F, Liu S, Glaeser H, Dawson PA, Hofmann AF, Kim RB, Shneider BL, Pang KS (2006) Transactivation of rat apical sodium-dependent bile acid transporter and increased bile acid transport by 1α,25-dihydroxyvitamin D3 via the vitamin D receptor. Mol Pharmacol 69:1913–1923CrossRefPubMedGoogle Scholar
- Chiang KC, Yeh CN, Hsu JT, Yeh TS, Jan YY, Wu CT, Chen HY, Jwo SC, Takano M, Kittaka A, Juang HH, Chen TC (2013) Evaluation of the potential therapeutic role of a new generation of vitamin D analog, MART-10, in human pancreatic cancer cells in vitro and in vivo. Cell Cycle 15:1316–1325CrossRefGoogle Scholar
- Chow EC, Durk MR, Cummins CL, Pang KS (2011a) 1A,25-dihydroxyvitamin D3 up-regulates P-glycoprotein via the vitamin D receptor and not farnesoid X receptor in both fxr(-/-) and fxr(+/+) mice and increased renal and brain efflux of digoxin in mice in vivo. J Pharmacol Exp Ther 337:846–859CrossRefPubMedGoogle Scholar
- Coburn JW, Maung HM, Elangovan L, Germain MJ, Lindberg JS, Sprague SM, Williams ME, Bishop CW (2004) Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis 43(5):877–890CrossRefPubMedGoogle Scholar
- DeLuca HF, Bedale W, Binkley N, Gallagher JC, Bolognese M, Peacock M, Aloia J, Clagett-Dame M, Plum L (2011) The vitamin D analogue 2MD increases bone turnover but not BMD in postmenopausal women with osteopenia: results of a 1-year phase 2 double-blind, placebo-controlled, randomized clinical trial. J Bone Miner Res 26:538–545CrossRefPubMedGoogle Scholar
- Felsenberg D, Bock O, Borst H, Armbrecht G, Beller G, Degner C, Stephan-Oelkers M, Schacht E, Mazor Z, Hashimoto J, Roth HJ, Martus P, Runge M (2011) Additive impact of alfacalcidol on bone mineral density and bone strength in alendronate treated postmenopausal women with reduced bone mass. J Musculoskelet Neuronal Interact 11:34–45PubMedGoogle Scholar
- Fujita T, Orimo H, Inoue T, Kaneda K, Sakurai M, Morita R, Yamamoto K, Sugioka Y, Inoue A, Takaoka K, Yamamoto I, Hoshino Y, Kawaguchi H (2007) Clinical effect of bisphosphonate and vitamin D on osteoporosis: reappraisal of a multicenter double-blind clinical trial comparing etidronate and alfacalcidol. J Bone Miner Metab 25:130–137CrossRefPubMedGoogle Scholar
- Hayashi M, Tsuchiya Y, Itaya Y, Takenaka T, Kobayashi K, Yoshizawa M, Nakamura R, Monkawa T, Ichihara A (2004) Comparison of the effects of calcitriol and maxacalcitol on secondary hyperparathyroidism in patients on chronic haemodialysis: a randomized prospective multicentre trial. Nephrol Dial Transplant 19:2067–2073CrossRefPubMedGoogle Scholar
- Ke HZ, Qi H, Crawford DT, Simmons HA, Xu G, Li M, Plum L, Clagett-Dame M, DeLuca HF, Thompson DD, Brown TA (2005) A new vitamin D analog, 2MD, restores trabecular and cortical bone mass and strength in ovariectomized rats with established osteopenia. J Bone Miner Res 20:1742–1755CrossRefPubMedGoogle Scholar
- Kim YC, Kim IB, Noh CK, Quach HP, Yoon IS, Chow ECY, Kim M, Jin HE, Cho KH, Chung SJ, Pang KS, Maeng HJ (2014) Effects of 1α,25-dihydroxyvitamin D3, the natural vitamin D receptor ligand, on the pharmacokinetics of cefdinir and cefadroxil, organic anion transporter substrates, in rat. J Pharm Sci 103:3793–3805CrossRefPubMedGoogle Scholar
- Li P, Li C, Zhao X, Zhang X, Nicosia SV, Bai W (2004) p27(Kip1) stabilization and G(1) arrest by 1,25-dihydroxyvitamin D(3) in ovarian cancer cells mediated through down-regulation of cyclin E/cyclin-dependent kinase 2 and Skp1-Cullin-F-box protein/Skp2 ubiquitin ligase. J Biol Chem 279:25260–25267CrossRefPubMedGoogle Scholar
- Marchwicka A, Cebrat M, Sampath P, Snieżewski L, Marcinkowska E (2014) Perspectives of differentiation therapies of acute myeloid leukemia: the search for the molecular basis of patients’ variable responses to 1,25-dihydroxyvitamin d and vitamin d analogs. Front Oncol 4:125CrossRefPubMedPubMedCentralGoogle Scholar
- Muto A, Kizaki M, Yamato K, Kawai Y, Kamata-Matsushita M, Ueno H, Ohguchi M, Nishihara T, Koeffler HP, Ikeda Y (1999) 1,25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid-resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1). Blood 93:2225–2233PubMedGoogle Scholar
- Papadimitropoulos E, Wells G, Shea B, Gillespie W, Weaver B, Zytaruk N, Cranney A, Adachi J, Tugwell P, Josse R, Greenwood C, Guyatt G, Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group (2002) Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev 23:560–569CrossRefPubMedPubMedCentralGoogle Scholar
- Pendás-Franco N, García JM, Peña C, Valle N, Pálmer HG, Heinäniemi M, Carlberg C, Jiménez B, Bonilla F, Muñoz A, González-Sancho JM (2008) DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1α,25-dihydroxyvitamin D3. Oncogene 27:4467–4477CrossRefPubMedGoogle Scholar
- Pepper C, Thomas A, Hoy T, Milligan D, Bentley P, Fegan C (2003) The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. Blood 101:2454–2460CrossRefPubMedGoogle Scholar
- Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO, Dobnig H (2008b) Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab 93:3927–3935CrossRefPubMedGoogle Scholar
- Thompson PD, Jurutka PW, Whitfield GK, Myskowski SM, Eichhorst KR, Dominguez CE, Haussler CA, Haussler MR (2002) Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochem Biophys Res Commun 299(5):730–738CrossRefPubMedGoogle Scholar
- Wang X, Wang H, Shen B, Overholser BR, Cooper BR, Lu Y, Tang H, Zhou C, Sun X, Zhong L, Favus MJ, Decker BS, Liu W, Peng Z (2016) 1-A, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10. Transl Res 178:54–62CrossRefPubMedGoogle Scholar