Influence of drugs on vitamin D and calcium metabolism.

Dermato-Endocrinology 4:2, 158–166; April/May/June 2012; G 2012 Landes Bioscience Influence of drugs on vitamin D and calcium metabolism Uwe Gröber1,* and Klaus Kisters2 1 Academy of Micronutrient Medicine; Essen, Germany; 2Westphalian Wilhelms University Münster; Academy of Micronutrient Medicine and Hypertension Excellence Center (ESH); Medizinische Klinik I; Herne, Germany . e nc Keywords: vitamin D, drugs, 25-hydroxy-vitamin D [25(OH)D], pregnane X receptor, 1,25-dihydroxyvitamin D [1,25(OH)2D], bisphosphonates, cytostatics, statins e i c s o i B . e s t e u d b i n r a t L s i 2 d 1 t 0 o 2 n o © D In the past, interactions between drugs and vitamin D have received only little or no attention in the health care practices. However, since more and more drugs are used for the treatment of patients, this topic is increasingly relevant. Several drugs can interfere with the vitamin D and bone metabolism. Drugs that activate the pregnane X receptor can disrupt vitamin D metabolism and vitamin D function. Beside this, the medication oriented supplementation of vitamin D can ameliorate the pharmacologic action of some drugs, such as bisphosphonates, cytostatics and statins. Introduction Vitamin D has long been known for its effects on calcium and bone metabolism. Vitamin D deficiency causes a lack of bone mineralization, which manifests as rickets in children and osteomalacia in adults.1,2 However, it is now becoming increasingly clear that the “sunshine vitamin” has a much broader range of actions in the human body than believed before. Its physiological effects are not only limited to bone. Besides its well-known effects on calcium/phosphate homeostasis, vitamin D influences muscle function, cardiovascular homeostasis, the immune response and the nervous function.3 A deficiency of vitamin D has been associated with muscle weakness and a high incidence of various chronic diseases such as cardiovascular disease, cancer, multiple sclerosis, and type 1 and 2 diabetes.4 Interactions between drugs and vitamin D have received only little or no attention in the medical and pharmaceutical world in the past. Since more and more drugs are used for the treatment of patients, this topic is increasingly relevant. As such interactions impact the health of the patient and the action and side effects of the drug, physicians and pharmacists should pay more attention to this fact in the future. As vitamin D deficiency leads to bone damage, it is particularly important to ensure an adequate vitamin D supply in cases of pre-existing osteoporosis or during long-term intake of drugs that promote the development of bone damage. Even after bone damage has already occurred, therapeutic use of vitamin D is often not considered.5 *Correspondence to: Uwe Gröber; Email: Submitted: 04/12/12; Revised: 05/07/12; Accepted: 05/11/12 http://dx.doi.org/10.4161/derm.20731 158 A number of drugs are known to interfere with the vitamin D metabolism through activation of the pregnane X receptor and thereby causing vitamin D deficiency.6,7 Through prevention or treatment of vitamin D deficiency, the risk of drug-induced bone damage, such as that caused by antiepileptic agents, glucocorticoids, anti-estrogens or antiretroviral drugs, can be reduced.8 For adequate bisphosphonate response in osteoporosis therapy a sufficient vitamin D status must be ensured.9 Initial studies indicate that vitamin D also has an effect on the lipid-lowering activity of statins (HMG-CoA reductase inhibitors) and the antibacterial effect of antituberculotic agents.10,11 The following article discusses the mechanisms of an interaction between vitamin D and the relevant drug groups. In many cases, monitoring of serum 25-hydroxy-vitamin D [25(OH)D] levels and compensation of vitamin D deficiency can contribute to reducing the risk of adverse drug reactions and/or improving the efficacy of various drugs. Pregnane X Receptor Mediated Interactions Vitamin D from the skin and diet is metabolized in the liver to 25-hydroxy-vitamin D [25(OH)D]. 25(OH)D is the major circulating form of vitamin D and is used to determine a patient’s vitamin D status.3 25(OH)D is metabolized in the kidneys by the enzyme 25-hydroxyvitamin D-1a-hydroxylase (CYP27B1) to its active form, 1a,25-dihydroxy-vitamin D [1,25(OH)2D].2 Both 25(OH)D and 1,25(OH)2D are oxidized by hydroxylases (CYP24A1, CYP3A4) at position 24 of the side chain. The resultant metabolites are physiologically inactive and are excreted as acids following further metabolic stages. Expression of the 24-hydroxylases is partially dependent on the calcium and parathyroid hormone levels in the blood and partially regulated by 1,25(OH)2D itself. In this way, the concentration of circulating 1,25(OH)2D and thus both calcium and phosphate homeostasis in the blood is strictly regulated. Various drugs can interfere in this balance through activation of the pregnane X receptor (PXR). In 1998 the pregnane X receptor (PXR) of mouse was first identified as a member of the nuclear receptor (NR) superfamily on the basis of its sequence homology with other NRs. Human PXR (hPXR) was found subsequently and named steroid and xenobiotic receptor (SXR) or pregnaneactivated receptor.12,68,69 The Pregnane X receptor (PXR) plays an important role in detoxifying xenobiotics and drugs. It is an Dermato-Endocrinology Volume 4 Issue 2 REVIEW Table 1. Drugs that activate the pregnane-X-receptor (PXR) (selection) PXR-Ligands Examples Antiepileptics Phenytoin, Carbamazepine Antineoplastic drugs Cyclophophamide, Taxol, Tamoxifen Antibiotics Clotrimazole, Rifampicin Anti-inflammatory agents Dexamethasone Antihypertensives Nifedipine, Spironolactone Antiretroviral drugs Ritononavir, Saquinavir Endocrine drugs Cyproterone acetate Herbal medicines Kava kava, St. John’s wort (Hyperforin) Antiepileptic Drugs It was documented more than 40 y ago that institutionalized children who were on multiple anti-seizure medications developed rickets that was resistant to normal vitamin D therapy.13 As a result of their disease and the associated tendency to fall, patients with epilepsy are at higher risk of bone fractures. In addition, many antiepileptic drugs (AEDs) promote the pathogenesis of AED-induced bone disease, which is detected in up to 50% of patients undergoing long-term antiepileptic treatment. The risk of bone fractures is two to six times higher in patients with epilepsy than in the average population and comparable to that seen in patients undergoing long-term glucocorticoid therapy.5,14-16 AED-induced disturbances of bone integrity are mainly influenced by the type, dosage and duration of the antiepileptic therapy. A dose-dependent increase in the risk of fractures was particularly observed during therapy with carbamazepine, oxcarbazepine, clonazepam, Phenobarbital, phenytoin, primidone, and valproic acid. The risk of AED-induced bone disease was greater with inducers of cytochrome P450 (CYP), i. (...truncated)