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Contribution of the Biliary Pathway to the Homeostasis of Vitamin D3 and of 1,25-Dihydroxyvitamin D₃^*

MARIELLE GASCON-BARRE and MARIO GAMACHE

Centre de Recherche Clinique Andre-Viallet, Hopital Saint-Luc, and Departement de Pharmacologie, Faculte de Medecine, Universite de Montreal Montreal, Quebec, Canada H2X 1P1

Address all correspondence and requests for reprints to: Dr. Marielle Gascon-Barre, Centre de Recherche Clinique Andre-Viallet, Hopital Saint-Luc, 264 Rene-Levesque Boulevard East, Montreal, Quebec, Canada H2X 1P1.

Abstract

The role of the biliary pathway in the homeostasis of the vitamin D₃ (D₃) group of compounds is poorly understood. The purpose of the studies was to investigate the biliary excretion pattern of materials derived from the parent compound D₃ and from the hormone 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) during constant iv infusion, and to probe the influence of 1,25(OH)₂D₃ pretreatment on the excretion into the bile of D₃-derived materials. Under anesthesia, the bile duct, duodenum (for bile replacement), and jugular veins were cannulated. The experiments were then carried out in fully awake rats with access to food and water ad libitum during a period of 6 h. Data indicate that before steady state was reached, biliary excretion of 1,25(OH)₂[³H]D₃ was much more important than that of [¹⁴C]D₃ with bile/plasma concentration ratios above 1 in l,25(OH)₂[³H]D₃-infused animals from the 15th–60th min of infusion compared to ratios between 0.12–0.40 in [¹⁴C]D₃-infused rats (P < 0.0001); this led to a cumulative excretion 6.3-fold higher after 1,25(OH)₂[³H]D₃ than after [¹⁴C]D₃ administration, with 3.9 ± 0.4% and 0.6 ± 0.1% of the dose being recovered into the bile during the first hour of excretion. However, once stable plasma concentrations were reached, the rate of excretion of the two compounds became similar, with bile/plasma concentration ratios of 0.64 ± 0.02 and 0.70 ± 0.02 (P > 0.05), and plasma bile clearance of 26.4 ± 1.0 and 25.7 ± 1.7 µl/min-kg for 1,25(OH)₂[³H]D₃ and [¹⁴C]D₃, respectively (P > 0.05). During that period, the MCR of 1,25(OH)₂D₃ was estimated to be 118.3 ± 10.5 jul/min-kg. On the other hand, 1,25(OH)₂D₃ pretreatment as constant ip infusion (14 pmol/24 h for 6 days) significantly increased bile flow [1,25(OH)₂D₃ treated, 44.9 ± 1.6 µl /min-kg; untreated, 36.6 ± 0.5 µl/min · kg, P < 0.01)], leading to significant increases in the plasma bile clearance of [¹⁴C]D₃-derived compounds early in the course of the study (P < 0.004) in the presence of similar bile/plasma concentration ratios in the two groups. During the steady state phase of investigation, however, bile/plasma concentration ratios became lower in 1,25(OH)₂D₃- than in placebo-treated animals (P < 0.05), but due to the l,25(OH)₂D₃-mediated increase in bile flow, similar plasma bile clearances were observed in both groups. Finally, the cumulative biliary excretion of [¹⁴C]D₃-derived materials was found to be similar in 1,25(OH)₂D₃- and placebo-treated animals over the 6- h period of observation, averaging 4.3 ± 0.1% and 5.0 ± 0.3% of the dose administered, respectively (P > 0.05) [compared to 11.2 ± 0.6% for the cumulative biliary transfer of 1,25(OH)₂[³H]D₃ (P < 0.0001)]. Collectively, our data indicate that 1,25(OH)₂D₃ influences D₃ homeostasis by perturbing its clearance through increases in bile flow although the hormome per se does not increase the excretion of the parent compound. Data also indicate that 1,25(OH)₂D₃ is much more readily transferred into the bile than D₃, the biliary pathway rapidly responding to sudden increases in circulating hormone concentrations. Under steady state conditions, however, the plasma bile clearance of D₃ and 1,25(OH)₂D₃ becomes similar, most likely reflecting common pathway(s) for the biliary excretion of members of the vitamin D₃ family. (Endocrinology 129: 2335–2344,1991)

Footnotes

^* These studies were supported by a grant from the Medical Research Council of Canada

Recipient of a Scientific award from the Medical Research Council of Canada.

Recipient of a Studentship award from the Quebec Fonds pour la formation de chercheur et l’aide à la recherche.

Received June 3, 1991.

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