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

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.

Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1).

The ATP-binding cassette (ABC) transporter ABCC1, or multidrug resistance-related protein 1 (MRP1) is implicated in Phase II metabolism and multidrug resistance as it effluxes substrate anticancer drugs. As cannabinoids inhibit two related ABC transporters, P-glycoprotein and ABCG2, here we examined whether they also inhibit ABCC1. Indeed, the cannabinoids enhanced the intracellular accumulation of two ABCC1 substrates, Fluo3 and vincristine, in ovarian carcinoma cells over-expressing ABCC1 (2008/MRP1) with a rank order of potency: cannabidiol>cannabinol>Delta(9)-tetrahydrocannabinol. Cannabinoid inhibition of ABCC1 was confirmed using insect cell membrane MRP1 ATPase assays. These results demonstrate that cannabinoids inhibit ABCC1.