Trial Information

Characterization of the Pharmacokinetics of Oral Selenium Compounds in Humans Before and Following Supplementation

The chemopreventive efficacy of Se was tested in a 10-year human intervention trial; total
and lung cancer mortality, total cancer incidence, colorectal cancer and prostate cancer
incidence decreased. This study is designed to compare, via stable isotope tracer studies
the kinetics of inorganic and organic Se before and following two years of oral
supplementation with L-selenomethionine, to measure forms of Se in the plasma (extracellular
Se-dependent glutathione peroxidase [GSHPx], selenoprotein-P [SeP], albumin-bound Se [AlbSe]
and nonprotein-bound low molecular weight [LMWSe] fractions), and to determine the effects
of supplementation on the ecology of the hindgut microflora. The forms of Se were chosen to
resemble the metabolism of the principal forms of Se in mixed American diets. Sodium
selenite, an inorganic form, is metabolized by reduction to selenide which is then either
used in the co-translational synthesis of SeCys in specific Se-containing proteins (e.g.,
glutathione peroxidases, diodinases, selenoproteins P and W), or is converted to methylated
excretion products; in this sense it resembles the food form selenocysteine (SeCys) which is
metabolized to the selenide level. Selenomethionine (SeMet), an organic form, is a major
form of Se in many foods, particularly those of plan origin. In addition to being
metabolized to selenide, SeMet also enters the metabolic protein pool by competing with the
sulfur-containing amino acid, methionine. A study is proposed to assess the impact of
selenium (Se) supplementation on its metabolism in humans.

A pilot study will be conducted to test recruitment strategies and sample collection,
preparation and analysis and to assess the detectability of two stable isotopes given
together. Four subjects will receive two 300 ug oral doses consisting of 150 ug of the
stable isotope 76Se as selenite and 150 ug of the stable isotope 74Se as selenomethionine on
study days one and twelve. Subjects will be followed for six weeks.

In the first pharmacokinetics tracer study (PK1), twenty-eight subjects will receive the
same two labeled stable isotope doses, and will be followed for 4 months. In addition, two
subjects who have been self-supplementing with 200 ug of Se as selenized yeast for two years
will take part in PK1 to assess the sensitivity over time of the tracer assay in
supplemented subjects. PK1 will be followed by a 2-yr supplementation period, in which all
28 subjects will receive daily doses of 200 ug of L0SeMet; subjects = metabolism is expected
to approach a new steady state reflective of long-term supplementation. A second 4-month
pharmacokinetic tracer study (PK2) will then be conducted while subjects remain on
Se-supplementation with an extension of six monthly blood samples. Extensive sampling of
plasma, urine, and feces during PK1 and PK2 will permit both the refinement of existing
baseline models for selenite and selenomethionine metabolism in humans and the investigation
of changes in metabolism arising from Se-supplementation. The study is designed to detect a
difference of 0.75 standard deviation units in pre-versus post-supplementation rate
parameters, assuming a two-sided test with an alpha level of 0.05 and a power of 0.80.

The non-absorbed portion of Se may favor portions of the normal colonic bacterial microflora
that produce certain short-chain fatty acids that colon cells use for energy. To test this
hypothesis, fecal specimens will be analyzed for short-chain fatty acids over the course of
Se-supplementation. In addition, the sampling of buccal cell-Se and of toenail-Se on a
quarterly basis over the course of the study and assay of thyroid hormone levels during the
first year of the study will permit the investigation of possible changes in levels
resulting from supplementation.