Drug-vitamin D interactions: a systematic review of the literature

Abstract

Extensive media coverage of the potential health benefits of vitamin D supplementation has translated into substantial increases in supplement sales over recent years. Yet, the potential for drug-vitamin D interactions is rarely considered. This systematic review of the literature was conducted to evaluate the extent to which drugs affect vitamin D status or supplementation alters drug effectiveness or toxicity in humans. Electronic databases were used to identify eligible peer-reviewed studies published through September 1, 2010. Study characteristics and findings were abstracted, and quality was assessed for each study. A total of 109 unique reports met the inclusion criteria. The majority of eligible studies were classified as class C (nonrandomized trials, case-control studies, or time series) or D (cross-sectional, trend, case report/series, or before-and-after studies). Only 2 class C and 3 class D studies were of positive quality. Insufficient evidence was available to determine whether lipase inhibitors, antimicrobial agents, antiepileptic drugs, highly active antiretroviral agents, or H2 receptor antagonists alter serum 25(OH)D concentrations. Atorvastatin appears to increase 25(OH)D concentrations, whereas concurrent vitamin D supplementation decreases concentrations of atorvastatin. Use of thiazide diuretics in combination with calcium and vitamin D supplements may cause hypercalcemia in the elderly or those with compromised renal function or hyperparathyroidism. Larger studies with stronger study designs are needed to clarify potential drug-vitamin D interactions, especially for drugs metabolized by cytochrome P450 3A4 (CYP3A4). Healthcare providers should be aware of the potential for drug-vitamin D interactions.

Figure 1. Vitamin D metabolism

Ovals denote metabolic enzymes, rectangles denote substrates.

Figure 2. Vitamin D intracellular signaling pathways

As a steroid hormone, 1,25(OH)₂D is involved in intracellular signaling through both rapid responses (initiation of membrane-associated signal transduction as a result of 1,25(OH)₂D binding to membrane-bound vitamin D receptors (mVDR)) and genomic responses (initiation/inhibition of transcription for genes containing a vitamin D response element (VDRE)). In the slower genomic responses, vitamin D metabolites can enter the cell either as 25(OH)D (through carrier-mediated endocytosis with megalin or cubilin as the primary carriers, and subsequent intracellular conversion to 1,25(OH)₂D), or directly as the active 1,25(OH)₂D. Binding of 1,25(OH)₂D to the vitamin D receptor (VDR) in the cytoplasm forms a heterodimer with the retinoid X receptor (RXR), which is then translocated into the nucleus where it binds to VDREs in the promoter region of certain genes and either activates or inhibits gene transcription in complex with RNA polymerase (RNA Pol).

Figure 3

Flow chart of manuscript identification and inclusion