To clarify the effect of the long-term administration of a commercial multivitamin tablet containing 5 mg of thiamin tetrahydrofurfuryl disulfide (TTFD), 3.5 mg of riboflavin, and other vitamins, two or four tablets daily were administered orally to healthy subjects for 44 weeks. The blood thiamin concentrations increased gradually during administration and showed a maximum concentration at 44 weeks. The blood thiamin concentrations in the 4 tablets/day group were higher than those in the 2 tablets/day group at all times. Dose-dependence of the blood thiamin concentrations in the three groups including placebo group during the experimental period was shown to be significant by linear regression analysis. The urinary thiamin excretion in the 2 and 4 tablets/day groups was higher than in the placebo group at all times. The blood riboflavin concentrations also increased steadily during the administration period, but the increase was less than that noted for the thiamin concentration. Urinary excretion of riboflavin was higher in the multivitamin groups than in the placebo group. Therefore, it is concluded that the daily oral administration of TTFD and riboflavin in a multivitamin preparation produces a significant increase of thiamin and riboflavin levels.

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In order to study the effect of a long-term (44 weeks) oral administration of a multivitamin preparation on vitamin B_6 and nicotinic acid status in normal subjects (7 healthy male adults aged in 21-24 years for each group), the total B_6 and nicotinic acid levels in whole blood were determined by HPLC methods, as well as urinary excretions of their metabolites. In the samples collected at 24 hours after taking of the medicine, the whole blood concentration of total B_6 in double dosage group (hereinafter group I), taking 18 mg of PN-HCl (pyridoxine hydrochloride) and 150 mg of NiA-NH_2 (nicotinamide) daily, was elevated to 6 times of the baseline at 4th week, and reached a plateau and kept on a level until 44th week. After cessation of the medicine the total B_6 level descended to the baseline after two weeks. The total B_6 level in the group of ordinary dosage (group II), taking 9 mg of PN-HCl and 75 mg of NiA-NH_2, was elevated to 3 times of the baseline at 4th week, and at the same time reached a plateau, and after two weeks from the cessation returned to the baseline. No significant change was found in placebo group (group III) throughout all experimental period. No significant elevation was found in all groups on blood total nicotinic acid level at 24 hours after taking the medicine. The urinary excreted PIC (4-pyridoxic acid) in group I was 11.35 ± 2.82 mg/day at 4th week, and subsequently increased slightly into a level of 15.81 ± 2.45 mg/day at 44th week, and after one week from the cessation returned within normal range. In group II the urinary excreted PIC was 5.38 ± 1.51 mg/day at 4th week, and 6.79 ± 1.59 mg/day at 44th week, and returned within normal range after one week from the cessation. No significant difference was found between group I and II in the mean of 24 hours urinary PIC excretion ratios (as PN (pyridoxine)). In the group I the urinary excreted MNA (N'-methylnicotinamide) was 34.2 ± 1.9 mg/day at 4th week, and 34.5 ± 7.7 mg/day at 44th week, and after one week the cessation returned on the baseline. In group II the urinary excreted MNA was 20.4 ± 7.2 mg/day at 4th week, and 19.7 ± 3.0 mg/day at 44th week, and after one week from the cessation returned to the baseline. No significant difference was found between I and II group in the urinary excretion ratios of MNA (as NiA-NH_2). The bioavailabilities of B_6 and nicotinic acid contained an ordinary dosage of multivitamin preparation were confirmed by the dose responsive change of blood B_6 level, urinary PIC and MNA excretion.

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A randomized and placebo-controlled study was carried out to investigate the changes in the plasma concentrations and urinary excretion of vitamin C during the long-term ingestion of a commercial multivitamin tablet containing vitamin C. Twenty-one healthy males aged 21-24 years were randomly divided into 3 groups. The three groups took either placebo or vitamin C (250 mg or 500 mg) daily for 44 weeks, and measurements were made at 0, 4, 12, 22, 28 and 44 wks. The mean vitamin C plasma concentrations and urinary excretion in the subjects before ingestion were 0.70 ± 0.09 mg/100 ml (mean ± SD) and 12.4 ± 2.8 mg/day, respectively. There were marked increases in the plasma concentrations and urinary excretion at 4 wks, followed by further gradual increases during the experimental period. The mean plasma concentrations were 1.26 ± 0.14 mg/100 ml in the 250 mg group and 1.40 ± 0.19 mg/100 ml in the 500 mg group at 44 wks, and these levels were significantly higher than in the placebo group (0.83 ± 0.10 mg/100 ml). Dose-dependence of the plasma concentrations in the three groups during the experimental period was significant by linear regression analysis. Urinary excretion increased to 134 ± 48 mg/day in the 250 mg group and to 240 ± 71 mg/day in the 500 mg group at 44 wks, which was significantly higher than in the placebo group (13.4 ± 1.9 mg/day) in both cases. Dose-dependent differences among the three groups in the urinary excretion during experimental period were also significant by linear regression analysis. Changes in the plasma concentrations and urinary excretion of vitamin C after the discontinuation of ingestion were also investigated, indicating that there was no withdrawal effect. No side effects were observed in both the placebo and vitamin C groups.

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The bioavilability of vitamin A and E was studied in 21 healthy males aged 21-24 years by the daily oral administration of a multivitamin preparation for 44 weeks. The subjects were randomly divided into three groups in term of the daily dosage : a group receiving 4,000 IU of vitamin A and 20 mg of vitamin E acetate, a group receiving 2,000 IU of vitamin A and 10 mg of vitamin E acetate, and a placebo group. 1. With respect to plasma retinol levels, there were no significant changes and differences among the three groups throughout the study period. 2. With respect to plasma tocopherol levels, the following was noted. (a) α-Tocopherol level : There were no significant changes and differences in the levels between the placebo and 10 mg groups throughout the study period. In the 20 mg group, however, plasma α-tocopherol levels showed a significant elevation at 22, 38, and 44 weeks when compared with those in the placebo group. (b) γ-Tocopherol level : No significant differences were observed among the three groups during the study period.

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Normal male subjects aged in 21-24 years were randomly divided into three groups received daily oral administration of 400 or 200 IU of vitamin D_2 or placebo by a multivitamin tablet (Panvitan^<(R)> Hi Tablet, Takeda Chem. Ind., Ltd.) for 44 weeks. Plasma levels of vitamin D_2/D_3, 25-OH-D_2/D_3, 24, 25 (OH)D_2/D_3 and 1,25 (OH)_2D_2/D_3, calcium, phosphorus, alkaline phosphatase (ALP) and parathyroid hormone (PTH) were assayed at 0, 4, 12, 22, 38 and 44 weeks after the initial administration. The plasma levels of 25-OH-D_2 in the 400 and 200 IU groups were significantly increased than those of the placebo group during the experimental period and these in the 400 IU group were significantly higher than those in the 200 IU group. Plasma 1,25 (OH)_2D_2 levels in the 400 IU group were significantly higher than the initial levels in all the experimental period, but total levels of 1,25 (OH)_2D_2 and 1,25 (OH)_2D_3 in the groups were strictly controlled within the normal range. The plasma levels of 24, 25 (OH)_2D_2 were not detected in all of the plasma samples. The urine calcium and phosphorus levels in the three groups were not significantly changed during the period and the other plasma biochemical data were also within the respective normal ranges. Therefore, we have concluded that daily oral administration of 400 and 200 IU of vitamin D_2 by the multivitamin tablet gives a significant increase of vitamin D nutritional status in subjects without risk of hypercalcemia.

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