Vitamin D Relation to Busulphan in Pediatrics Undergoing Hematopoietic Stem Cell Transplantation

Vitamin D is an essential compound that plays an important role in biological activities. There are two main sources of vitamin D: either through the conversion of 7-dehydrocholesterol in the skin by UVB light or through absorption in the small intestine via food intake or dietary supplements. Vitamin D from both sources undergoes a first hydroxylation in the liver through cytochrome P 450 forming 25 (OH) vitamin D, followed by a second hydroxylation that takes place in the kidneys resulting in the active form of the vitamin D (1.25 (OH)₂ Vitamin D). Busulphan is an alkylating agent used mainly as part of the myeloablative conditioning prior to hematopoietic stem cell transplantation (HSCT). Recent studies have shown that vitamin D can have some interaction (additive, synergistic, or antagonistic) with a number of chemotherapeutic agents; therefore, we have investigated the relation between vitamin D and busulphan.

In the present investigation, the relation between vitamin D and busulphan was evaluated in 44 pediatric patients undergoing stem cell transplantation. The patients received busulphan (1.8-2mg/kg twice a day for four days) as a prat of their condition regimen prior to HSCT. Patients were divided into two groups; the first group received the drug orally (n=20) while the second was treated intravenously (n=24). Blood samples were collected from these patients, and busulphan was quantified in the plasma using gas chromatography with electron capture detector, while 25 (OH) Vitamin D levels were measured using ELISA.

Our results showed that the levels of vitamin D before the start of the conditioning were positively correlated with the first busulphan AUC in the group of patients receiving the drug orally (R²=0.25, P<0.05). Moreover, a significant (p<0.0001) increase was observed in the plasma levels of vitamin D (290 -1190 ng/mL) at 24h after the start of busulphan conditioning compared to that found before the start of busulphan treatment (15-162 ng/mL).On the other hand, no significant changes in the vitamin D levels were observed in the patients receiving busulphan intravenously. To confirm the previous findings, two groups of mice were treated with busulphan (25mg/Kg/day) dissolved in 5% DMSO either orally (PO) or intraperitoneally (IP) once daily for 4 days. Mice were fed with standard chew (Teklad Global 18% Protein Rodent Diet containing vitamin D₃ at a concentration of 1.5 IU/g) and food intake was monitored daily. Two control groups (received oral 5% DMSO or intraperitoneal 5% DMSO and negative controls) were run in parallel. Vitamin D levels were measured in mice plasma using ELISA. The results showed that vitamin D levels were higher in mice treated with oral busulphan compared to those who received the drug via IP administration.

In conclusion, the present results indicate that vitamin D levels before conditioning may influence busulphan AUC when the drug is administered orally and hence the clinical outcome. On the other hand, the oral administration of busulphan has a significant effect on the vitamin D levels, which suggest that the observed effects are mainly based on alteration in vitamin D uptake. Currently, further studies are ongoing to investigate the underlying mechanisms. Altogether, suggest that busulfan levels and vitamin D intake should be monitored in patients treated with oral busulphan in order to avoid their toxicities and improve the clinical outcome.