Hepatic arterial and intravenous administration of 1,25-dihydroxyvitamin D₃ – evidence of a clinically significant hepatic first-pass effect

Abstract.

Purpose: We have previously shown that 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] inhibits the proliferation of a number of human cancers, including colorectal and hepatocellular carcinoma, both of which affect the liver and are major causes of cancer death. However, the clinical use of 1,25(OH)₂D₃ and analogues has been restricted by the development of hypercalcaemia upon systemic administration. We hypothesized that a clinically significant hepatic first-pass effect may exist upon the administration of 1,25(OH)₂D₃ as a hepatic arterial infusion, and that such an effect may allow high levels of 1,25(OH)₂D₃ to be delivered to the liver whilst avoiding high systemic levels. Methods: To examine this hypothesis, two groups of Landrace pigs were given identical doses of 1,25(OH)₂D₃ as continuous infusions, one group systemically, the other as a hepatic arterial infusion. Serum levels of 1,25(OH)₂D₃, calcium, phosphate and a number of liver and kidney function tests were performed regularly. Results: Concentrations of 1,25(OH)₂D₃ and calcium remained normal in the hepatic arterial infusion animals, in contrast to the intravenous infusion animals which developed elevated levels of 1,25(OH)₂D₃ and hypercalcaemia. Hepatic arterial infusion of 1,25(OH)₂D₃ did not produce any adverse effects upon renal or hepatic function. Conclusion: The present findings support the existence of a clinically significant hepatic first-pass effect when 1,25(OH)₂D₃ is administered as a continuous hepatic arterial infusion. Hepatic arterial infusion of 1,25(OH)₂D₃ has great potential in the treatment of hepatic cancers.