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


CONCLUSIONS
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.
Finlay
I G
IG
University of New South Wales, Department of Surgery, St George Hospital, Kogarah, Sydney, Australia.
Stewart
G J
GJ
Shirley
P
P
Woolfe
S
S
Pourgholami
M H
MH
Morris
D L
DL
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D002117:Calcitriol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002118:Calcium / Q000097:blood; D002120:Calcium Channel Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008099:Liver / Q000378:metabolism*; D010710:Phosphates / Q000097:blood; D013552:Swine; D014508:Urea / Q000097:blood
D002120:Calcium Channel Agonists; D010710:Phosphates; D014508:Urea; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002117:Calcitriol; D002118:Calcium