Total body phylloquinone and its turnover in human subjects at two levels of vitamin K intake

Abstract

The aims of this study were to determine the total body phylloquinone and its metabolic turnover in human subjects using a tracer dose of [5-H 3 ]phylloquinone containing 55·5 £ 10 4 MBq=mmol. Seven subjects aged 22 to 49 years were given 0·3 mg isotopic phylloquinone intravenously on a control diet (75 mg phylloquinone/d) and blood, urine and faeces were sampled periodically for 6 d. Five of these subjects were studied a second time after 3 -8 weeks on a low-vitamin K diet (8 mg/d). The changes in the radioactivity of plasma phylloquinone with time were analysed by the method of residuals and fitted to a curve composed of two exponential components. The size of the exchangeable body pool was calculated by isotope dilution. Plasma phylloquinone levels fell during vitamin K restriction but the vitamin K-dependent coagulation factors did not change. After injection the first exponential decay curve t 1/2 was 1·0 (SD 0·47) h in the subjects on the control diet and 0·49 (SD 0·27) h after vitamin K restriction. On the control diet, the second exponential t 1/2 was 27·6 (SD 124) h that did not change on the low-vitamin K diet (t 1=2 ¼ 25·1 (SD 13·5) h). These results indicate that the turnover time for phylloquinone in human subjects is about 1·5 d. Urinary excretion of 3 H-metabolites ranged from 30 % of the administered dose on the control diet to 38 % on the restricted diet and had the same turnover rate as the second component of the plasma decay curves. The exchangeable body pool of phylloquinone declined from about 1·0 mg/kg before restriction to lower values after vitamin K restriction. The faecal excretion of phylloquinone and its metabolites fell from 32 % of the administered dose on the control diet to 13 % on the restricted diet. Vitamin K: Radioactive phylloquinone: Exchangeable body pool: Metabolic turnoverGreat advances have been made in the understanding of the distribution, function and metabolism of vitamin K since its discovery by Henrik Dam. (Dam, 1935;Olson, 1999) Less well documented is the content of vitamin K in the human body and the extent of its metabolic turnover. The first attempt to measure phylloquinone turnover in human subjects was made by Shearer et al. (1972), who administered 1 mg [1 0 , 2 0 -3 H 2 ]phylloquinone (200 MBq/ mmol) intravenously to each of three young male volunteers whose plasma was sampled at intervals for 96 h. They observed that after 2 h only 10 % of the initial radioactivity remained in the plasma space, and that the decay curves over 6 h could be resolved into two exponential functions with half-times of 20-24 min and 121-150 min. Later Shearer et al. (1974) repeated their study using 45 mg-phylloquinone of higher specific activity (3515 MBq/mmol) and obtained similar results. Bjornsson et al. (1979) carried out similar turnover studies in four healthy male volunteers using 300 mg [1 0 , 2 0 -3 H 2 ]phylloquinone (3237 MBq/mmol). They also observed two exponential components to the decay curves of 26 (SD 8) min and 166 (SD 10) min over 10 h.None of these invest...

A stable isotope method for the simultaneous measurement of vitamin K1 (phylloquinone) kinetics and absorption

“…The average values of the corresponding parameters found in the present experiments most closely resemble the values obtained by Shearer et al (1972Shearer et al ( , 1974, Shepherd et al (1977) and Bjornsson et al (1979) rather than those more recently reported by Olson et al (2002) (see Table 3). …”

“…Thus, if irreversible disposal occurred at a greater rate than that predicted, absorption would be under-estimated. However, our data are similar to those previously published with the exception of the Olson et al (2002) which suggested slower rates of disposal, and that would lead, in our model, to lower estimates of absorption.…”

“…However, our estimate of total body pool size (5.1 nmol) is low in comparison to values (222 nmol) estimated from direct analysis of tissues (Olson et al, 2002). While Olson's kinetic studies indicated body pool sizes of 1.3-2.7 nmol/kg (equivalent to 93-189 nmol for a 70 kg person), these data should be treated with caution because body pool size was determined via the approximation that pool size can be calculated from the intercept of a terminal exponential in kinetic studies where the correspondence of tracer radioactivity to vitamin K 1 was not established.…”

“…In the case of Olson et al (2002), even though the dose levels of vitamin K 1 given were genuinely tracer quantities, no measurements were made before 10 min post dose and only plasma radioactivity was measured. In these circumstances, it would be difficult to detect the fast exponential component observed in this study and the others cited in Table 3, and later time points are likely to represent the increasing presence of radioactivity in circulating vitamin K 1 metabolites.…”

“…Radioactive tracers have been used to explore the kinetics of vitamin K 1 metabolism, but early investigations (Shearer et al, 1970(Shearer et al, , 1972(Shearer et al, , 1974Shepherd et al, 1977) were restricted both by a low specific activity of the tracer dose and the lack of a suitable methodology for the analysis of vitamin K 1 concentrations in plasma. More recently, Olson et al (2002) performed experiments that used physiological levels of radiolabelled vitamin K 1 of much higher specific activity, with high-performance liquid chromatography (HPLC) for quantitative measurements, and obtained kinetic data substantially different from those obtained previously (Olson et al, 2002).…”