Vitamin D: Pharmacokinetics and Safety When Used in Conjunction with the Pharmaceutical Drugs Used in Cancer Patients: A Systematic Review

Vitamin D has reported anti-cancer and anti-inflammatory properties modulated through gene transcription and non-genomic signaling cascades. The purpose of this review was to summarize the available research on interactions and pharmacokinetics between vitamin D and the pharmaceutical drugs used in patients with cancer. Hypercalcemia was the most frequently reported side effect that occurred in high dose calcitriol. The half-life of 25(OH)D3 and/or 1,25(OH)2D3 was found to be impacted by cimetidine; rosuvastatin; prednisone and possibly some chemotherapy drugs. No unusual adverse effects in cancer patients; beyond what is expected from high dose 1,25(OH)2D3 supplementation, were revealed through this review. While sufficient evidence is lacking, supplementation with 1,25(OH)2D3 during chemotherapy appears to have a low risk of interaction. Further interactions with vitamin D3 have not been studied.


Introduction
Vitamin D's role and importance in bone metabolism has been known for many years. The influence of vitamin D status and the associated impact on health and disease represents yet another important potential role for vitamin D. Wang et al., in a recent meta-analysis on vitamin D status and the associated risk of cardiovascular disease (CVD) found a direct inverse association between circulating (25(OH)D 3 levels and CVD risk to 60 nmol/L [1]. Further roles for vitamin D are also under exploration, such as its function in the immune system and providing resistance to infection, as well as its antiproliferative and anti-inflammatory activity [1][2][3][4][5].
The main source of vitamin D is through endogenous production in the skin. Vitamin D is synthesized by the action of UVB radiation activating the 7-dehydrocholesterol molecule in the skin and converting it to pre-vitamin Vitamin D 3 (cholecalciferol). In this form, it is transported in the blood to the liver, bound to either albumin or vitamin D binding protein (DBP) [6]. In the liver, it is thought to be hydroxylated by 25-hydroxylase, a member of the CYP2R1 enzyme family, through specific enzyme(s) that still need to be elucidated, to 25-dehydroxyvitamin D 3 [25(OH)D 3 , calcidiol] [7]. Serum levels of 25(OH)D 3 are affected by vitamin D 3 intake and production by the skin, as there is little regulation of the conversion of cholecalciferol to 25(OH)D 3 within the liver [7]. From the liver, 25(OH)D 3 is transported to the kidney, where again hydroxylation occurs, this time by the enzymatic action of 1α-hydroxylase, a member of the CYP27B1 family, to 1,25-dihydroxyvitamin D [1,25(OH) 2 D 3 , calcitriol] [7]. 1,25(OH) 2 D 3 is catabolized by the action of 24-hydroxylase, a member of the CYP24A1 family, to calcitroic acid and excreted in bile. 25(OH)D 3 is the major circulating form of vitamin D, while 1,25(OH) 2 D 3 is the major active form of vitamin D. The liver and the kidney are the primary locations for conversion of vitamin D along its activation pathway; however, they are not the only locations where the conversion of vitamin D 3 to 25(OH)D 3 is possible [6,8].
Vitamin D 3 is stored in the adipose tissues of the body and its half-life is approximately 2 days, while 25(OH)D 3 's half-life is approximately 3 weeks [6]. When supplementation with vitamin D 3 is in excess, adipose tissue can become saturated and Vitamin D 3 readily converted to 25(OH)D 3 [6]. It is believed that 25(OH)D 3 is responsible for the toxicity of vitamin D since there are no known regulator mechanisms within the body for this conversion to 25(OH)D 3 [6,9]. While, 1,25(OH) 2 D 3 serum concentrations are tightly regulated through feedback mechanisms related to serum calcium and phosphorus concentrations and has a half-life of between 10-20 h [6,7]. In situations where vitamin D 3 intake has been in excess, rarely, have there been correspondingly high 1,25(OH) 2 D 3 levels, however, high intakes of calcitriol can override the feedback mechanisms [10].
Vitamin D's role in the maintenance of bone mineralization is affected through the elevation of calcium and phosphorus in the blood at concentrations that result in mineralization of the skeleton [8].
In addition, the anti-cancer and anti-inflammatory effects of vitamin D are regulated through gene transcription via the vitamin D receptor (VDR) and through non-genomic signaling cascades [2]. Vitamin D acts to block the cell cycle and slow cellular growth, promote apoptosis, modulate angiogenesis and regulate prostaglandin metabolism and signaling [2]. Hence, these signals have led researchers to explore its use in cancer prevention and treatment through epidemiological studies and randomized controlled trials in cancer [11][12][13][14][15][16][17]. Further, in vitro studies suggest that vitamin D can act synergistically with several different chemotherapeutic agents [18], creating uncertainty as to if and how vitamin D supplementation might be incorporated into a chemotherapeutic regime for cancer patients.
The objective of this review is to summarize the available evidence on the interactions between vitamin D and pharmaceutical drugs used in patients with cancer including the impact of vitamin D on the pharmacokinetics of these drugs and also any changes in vitamin D pharmacokinetics due to the drugs themselves.

Results and Discussion
There were 26,353 records reviewed for inclusion in the systematic review. After excluding duplicate records and screening based on title/abstract and then full text, twenty-six articles fitted the inclusion criteria. Figure 1 details the search strategy flow. The appendix contains the detailed search strategy for the OVID MEDLINE ® search. The majority of the papers found were in English, with one case report in French [19]. Details of the studies are summarized in Appendix Tables A1 and A2. There were a variety of different pharmaceutical drug and vitamin D combinations studied. Table 1 provides an overview of the various drugs included in the review and the form of vitamin D used in the studies. Cholecalciferol is the most frequently supplemented form of vitamin D, however, in the studies included in this review, calcitriol was the most commonly used form. Prostate cancer, in particular, and patients with solid tumors were the most well represented populations within the studies included in this review.

Overview of the Interactions
In general, there was no evidence found for positive or negative interactions between the drugs used in the treatment of cancer and vitamin D in cancer patients. Several studies report gastrointestinal cramps and ulcerations after the administration of high dose 1,25(OH) 2 D 3 [20][21][22]. The use of calcifediol and thiazide medications in the elderly may present a cause for concern as one case report was found reporting hypercalcemia in two individuals [19].
Hypercalcemia, an expected side effect of high dose vitamin D therapy alone, was also the most frequently reported side effect that occurred in conjunction with the various pharmaceutical drugs included in the review.
In vivo studies have identified that a calcitriol peak plasma concentration of 10 nmol/L has significant anti-tumor activity [23,24]. In several studies, as a strategy to increase the serum vitamin D levels to parallel those peak plasma concentrations and AUC that, in vivo studies, suggested induced anti-tumor activity, dexamethasone was used to reduce the incidence of hypercalcemia at these higher doses of vitamin D [25]. The maximum tolerable dose (MTD) of calcitriol was found to be 74 µg /week; [23] however, with the addition of dexamethasone, the MTD was increased to 125 µg /week [26].
Hypophosphatemia was seen in two studies where docetaxel was used for prostate cancer but not in all studies that used this drug combination. In the Petrioli et al. study, 32 µg of calcitriol was administrated orally, once per week, in three divided doses, and most prostate cancer patients experienced hypophosphatemia [27]. While in the Tiffany et al. study, 60 µg of calcitriol was administered orally, once per week and 16.7% of the prostate cancer patients experienced hypophosphatemia [28].
In a case report, Boulard et al. reported elevated calcium levels, mental confusion, asthenia, constipation with fecal impaction with the use of calcifediol (vitamin D 2 ) and thiazide medications in two elderly women over the age of 75 years [19]. All medications were halted and 45 mg/day of prednisone was administered; both cases resolved within one week. One of prednisone's mechanisms of action is to reduce intestinal calcium absorption, and this seemed to help to resolve these women's symptoms [29]. However, it is unclear as to the exact role of vitamin D in these cases, as some of these side effects reported are known risks of thiazide medications.

Impact on Pharmacokinetics
Several studies examined the pharmacokinetics of vitamin D during the course of treatment. calciferol was not found to impact the pharmacokinetics of gefitinib, or docetaxel [22,23,26]. Studies reporting on the pharmacokinetics are summarized in Appendix Table A3.
Beer et al. evaluated the pharmacokinetics of 5 µg /kg of calcitriol by mouth (p.o.) and 36 mg/m 2 of docetaxel intravenous (i.v.) alone, and in combination in five patients. They found no difference between the pharmacokinetics of calcitriol alone or with docetaxel [22]. The pharmacokinetics of orally administered calcitriol, in escalating doses, in combination with paclitaxel is presented in Appendix Table A4 [30]. The pharmacokinetics were determined as part of a maximum tolerable dose finding study; which was halted when evidence of a reduction in calcitriol oral bioavailability become evident at the higher dose. Studies on the pharmacokinetics of iv administered 1,25(OH) 2 D 3 were also identified. Appendix Table A4 summarizes the pharmacokinetics of i.v. administered calcitriol in increasing doses from two different studies [23,26]. Fakih et al. found that gefitinib did not have any impact on calcitriol pharmacokinetics; this finding was also confirmed in a pharmacokinetic study conducted by Muindi et al. [23,26], who compared the serum calcitriol plus dexamethasone concentration versus time plots from this study with the calcitriol only results from the Fakih et al. study [23], and reported that dexamethasone had no impact on calcitriol PKs [26].
Several studies reported on the impact that pharmaceutical drugs had on vitamin D metabolism. Investigations into the impact of statin medication on vitamin D metabolism were conducted in two studies. Rosuvastatin was found to increase both serum 25(OH)D 3 and 1,25(OH) 2 D 3 levels in both studies [31,32]. This may not be a drug class effect, since fluvastatin did not have the same impact on serum vitamin D parameters [32].
Odes and colleagues investigated the impact of cimetidine on vitamin D metabolism in nine participants during the spring months where there was increasing sun exposure [33]. They found that the anticipated increase in serum 25(OH)D3 levels from the increased sunlight did not occur in these individuals. There was no impact on 24,25(OH)D 3 nor 1,25(OH) 2 D 3 .
A small study investigated the impact of prednisone on vitamin D metabolism in four healthy subjects. Avioli et al. found that 30 mg/day of prednisone altered vitamin D metabolism, reducing the half-life of 25(OH)D 3 by 40-60%, and also reduced the vitamin D metabolite responsible for intestinal calcium absorption [29]. Briefly in this study, the pharmacokinetics of 1,2 3 H-vitamin D 3 were established in four normal healthy adult volunteers over a five day period. Ten µCi of radiochemically pure 1,2 3 H-vitamin D 3 was administered orally after a 16 h fast and blood samples were obtained at 5, 15, 30 and 45 min and at 1, 2, 4, 8, 12, 16 and 24 h for the first 24 h period and then every 12 h for an additional four days. After a two week wash-out period, each volunteer was given 30 mg of prednisone for 10 days. On Day 5, 1,2 3 H-vitamin D 3 was once again administered and blood samples were obtained according to the previously described schedule for the remaining five days of the study.
A small study involving four patients with gynecological malignancies examined the vitamin D metabolites before, during and after various chemotherapy regimens that included cisplatin. They found that, while there was variation in 24,25(OH)D 3 and 25(OH)D 3 levels during the study, 1,25(OH) 2 D 3 levels were significantly reduced by the chemotherapy [34]. The authors suggested that the reduction in 1,25(OH)D 3 levels may be attributed to cisplatin's nephrotoxic profile that results in the kidney's reduced ability to convert 25(OH)D 3 to 1,25(OH) 2 D 3 .
A second study compared the change in serum vitamin D metabolites between colorectal cancer patients undergoing chemotherapy versus those who were not receiving chemotherapy through a retrospective chart review. The study found that patients receiving chemotherapy were more likely to have lowered 25(OH)D 3 levels than those not receiving chemotherapy [35]. A recently published paper found the same result, lower serum 25(OH)D 3 levels in breast cancer patients during and after chemotherapy treatment [36].
Our review found that high dose calcitriol used in conjunction with several different pharmaceutical drugs used in patients with cancer did not result in adverse events beyond what could be expected from the use of high dose vitamin D alone, i.e., hypercalcemia. There were, however, several areas identified that warrant further investigation.
Dexamethasone was used to reduce the incidence of hypercalcemia and achieve a higher maximally tolerated dose (MTD) in prostate cancer patients, while prednisone was used to manage the side effects of hypercalcemia [19,26]. Both medications act by reducing intestinal absorption of calcium as a means to reduce the hypercalcemic state [19,26]. Avoili et al. found that prednisone reduced the half-life of 25(OH)D 3 whereas dexamethasone had no impact on 1,25(OH) 2 D 3 levels [26,29]. Work in animal models suggests that dexamethasone may impact 1,25(OH) 2 D 3 levels through up regulation of CYP24A1 transcription resulting in increased catabolism of 1,25(OH) 2 D 3 , indicating that more research into dexamethasone's potential impact on vitamin D metabolism is warranted given its wide spread use in cancer patients and similar mechanism of action to prednisone [37]. Further, there is evidence that many cancer tumor types: breast, lung, colon and cervical as examples, over expresses CYP24A1 mRNA which may result in increased catabolism of vitamin D [37]. Several studies pointed to a reduction in serum 25(OH) D 3 levels in patients undergoing chemotherapy when exposed to a broad base of different chemotherapy drugs [34][35][36]. Whether this is as a result of alterations in lifestyle from undergoing cancer treatments or from the chemotherapy drugs themselves is not entirely clear. Cisplatin does induce nephrotoxicity and reduced vitamin D levels have been reported in patients exposed to cisplatin. However, other chemotherapy drugs that do not induce nephrotoxicity have also induced these phenomena [34][35][36]. Vitamin D's role in immune system modulation, potential chemopreventative role, and in bone metabolism suggests that monitoring of vitamin D serum levels during the course of treatment for cancer may be important in this vulnerable population.
While the search parameters of this review did not directly reveal an impact of vitamin D on P450 system nor drugs that have an impact on vitamin D levels through alternation of the enzymatic activity through the P450 system, there are several drugs that are known to impact vitamin D levels. The azole class of antifungal drugs, such as ketoconazole, flucinazole have been shown to inhibit the activity of CYP24A1 [37]. Genistein, a plant isoflavone found in Glycine max (soybeans) and in other plant products, has been shown, in vitro, to in inhibit transcription of both the CYP24A1 and CYP27B1 genes [37,38]. Work by Wang and colleagues have demonstrated that 1,25(OH)2D 3 can be catabolized by a CYP3A4 dependent pathway, which is inducible by rifampin [39]. This CYP3A4 pathway maybe responsible for the osteomalacia-inducing aspects of several pharmaceutical drugs [37,39].
This review not only demonstrates the minimal evidence amassed relating to direct correlations between vitamin D and pharmaceutical agents employed in people with cancer, but also the limited collection of evidence relating to vitamin D metabolism in situations where normal organ or physiological function may be compromised due to pharmaceutical agents.
A limitation of this review is that the studies were all conducted in small patient populations, limiting both the power and the generalizability of the results. Despite the rigorous design of some of the existing studies, more robust studies with larger sample sizes might help address individual variations which may impact vitamin D and chemotherapeutic regimes. This relative lack of research points to opportunities for further exploration on the impact of pharmaceutical drugs on vitamin D metabolism.

Sources
Using an iterative process, a sensitive search strategy was developed and executed using the OVID platform. We . The search employed both controlled subject headings (e.g., vitamin D, Cholecalciferol, Cytochrome p-450 enzyme system) and text words (e.g., vitamin D3, Calcitrol, CYP). The drug formulary of Cancer Care Ontario was used to identify cancer-related drugs, the names of which were also incorporated into the search. When appropriate, floating subheadings for concepts such as adverse drug reaction, drug interaction, and drug toxicity were included in the search strategy. We also searched the Cochrane Library on Wiley (including CENTRAL, Cochrane Database of Systematic Reviews, DARE, HTA, and NHS EED). No language or study group limits were applied to any of the searches. However, where possible, results were restricted to the human population. Previous reviews were hand-searched to identify other potentially relevant publications. A search of the WHO International Clinical Trials [40] and the MetaRegister of Controlled Trials databases [41] were also conducted to ensure that all relevant publications had been identified.
The strategy was peer reviewed prior to execution by an experienced information specialist using the PRESS Checklist [42].

Inclusion Criteria
We selected all human studies and case reports using any form of vitamin D and a pharmaceutical drug used in patients with cancer. Studies were also included if they reported on the impact of vitamin D metabolism during the use of a pharmaceutical drug. No restrictions were placed on language of publication or country of study. The search results were imported into a bibliographic management tool (Thomson Reuters EndNote, Version X3, San Francisco, CA, USA). All titles were first reviewed to determine which articles to examine in greater detail.

Exclusion Criteria
Studies were excluded if a pharmaceutical drug was not included in the study; the study related to monitoring vitamin D levels in cancer patients as a means to manage side effects of medications; or a synthetic analog of vitamin D was used the study.

Data Extraction
Data extraction was carried out by one reviewer and independently checked for accuracy by a second reviewer. Data collected included the study location, year of publication, type of cancer, study design, participant numbers, drugs and dosage, form of vitamin D used, endpoints, study protocol and relevant reported outcomes. Additional information for pharmacokinetics studies was extracted and included: number of observations, dose, route of administration, half-life, C max , Area under the Curve (AUC 0-24 and AUC 0-72 ) and clearance.

Conclusions
Of the hundred or so pharmaceutical drugs that are used in the treatment of cancer patients only a handful of these drugs have been studied in combination with vitamin D, primarily calcitriol (1,25(OH) 2 D 3 ). The impact if any, of supplementation with vitamin D3 has not been reported on. It is reassuring to note that no unusual adverse effects in cancer patients, beyond what is expected from high dose 1,25(OH) 2 D 3 supplementation, were revealed through this review.
Perhaps one of the most interesting findings from this review is that certain chemotherapeutic regimens appear to reduce serum 25(OH)D 3 and/or 1,25 (OH) 2 D 3 levels during administration. This potential depletion combined with a lack of evidence for both pharmacodynamic and kinetic interactions suggests the need to monitor vitamin D levels during active cancer therapy and perhaps supplement with this agent during chemotherapy. Further research in this area is indicated as vitamin D status may have implications on the efficacy of conventional therapy for people living with cancer.             The first 25-OH vitamin D assay was used as the baseline in patients with multiple 25-OH vitamin D testing. Chemotherapy status was documented in all patients. Colorectal cancer patients were divided into two categories: "no chemotherapy group:" all patients who did not receive any chemotherapy or whose last chemotherapy treatment was at least 3 months prior to 25-OH vitamin D assay. "Chemotherapy group:" all patients whose baseline 25-OH vitamin D level was obtained during chemotherapy treatment or within 3 months after last dose of chemotherapy.