S-14-1 Bioavailability of Vitamins-An Overview

S-14-1 Bioavailability of Vitamins-An Overview M.MINO,1 A.MURATA,2 K.YASUDA,3 and Y.ITOKAWA4 1. Department of Pediatrics, Osaka Medical College, Takatsuki, 569, Japan 2. Department of Applied Biological Sciences, Saga Unioversity, Saga, 840, Japan 3. Department of Clinical Pathology, Faculty of Medicine, Teikyo University, Itabashi, Tokyo, 173, Japan 4. Department of Hygiene, Faculty of Medicine, Kyoto University, Kyoto, 606, Japan I. Introduction To maintain a healthy state for a long life, many healthy people in developed countries prefer to continually take vitamins. In past, there have been many reports on the bioavailability of individual vitamins at a large dose and single administration. These are however unsuitable for understanding the efficacy and bioavailabilities of individual vitamins in view of recent real situation of general vitamin intakes. Usually, several vitamins are together taken as a multivitamin-preparation continuously over a long period. When considering single vitamin intake for a long period, it is useful to know whether the baseline of blood vitamin levels changes, and whether a dose response appears. In addition, it may be important to know the problem of individuals with intakes of vitamin preparations with regard to the assessment of the nutritional status of vitamins. This also includes the danger of toxicity regarding the fat soluble vitamins A, D and E. However, there have been no reports, to our knowledge, on the bioavailablities of the usual daily dose of vi-in preparations over a long period. From the above view, Takeda Chemical Industries who sponsor this symposium, promoted an investigation on the bioavailabilities of vitamins with long term intake of a multivitamin preparation for 44 weeks. Some of results of this study will be here. II. Experirnentals: The multivitamin preparation used listed in Table 1. The content of each vitamin was not high compared with the RDA values. This paper will show vitamins C, B6, nicotinamide, vitamins A and E. A randomized, placebo-controlled study on the bioavailavilities of vitamins with long-term intake of a mutivitamin preparation for 44 weeks was carried out. Two dose levels and a placebo were examined to understand the dose responses. The pre-administration and postadministration study were also performed. Table 1. Multivitamin Tablet Composition >>Sugar-coated Tablet (Panvitan(R)-Hi; Takeda Chemical << Ind., Ltd.) III. Results and Discussion To understand difference in bioavailability of a vitamin, the same dose was taken either as a single vitamin preparation or together with other vitamins as a multivitamin preparation, a study was undertaken on vitamin C as

Symposium (14) Bioavailability an example[1]. No differences were observed in the bioavailablity between two forms of vitamin C. The ongoing study was then performed using only the multivitamin perparation. 1. Vitamin C [2]: Fig 1 shows the vitamin C changes in plasma and urine during Fig.1 Changes in plasma concentration and daily urinary excretion rate of vitamin C after administration administration. There were marked increases in the plasma concentration and urinary excretion at 4 weeks, followed by further gradual increases during the experimental period at both doses. These levels were significantly and effectively higher than in the placebo group. Dose-dependent differences in plasma concentrations and urinary excretion among the three groups were statistically significant by linear regression analysis. In this examination, no withdrawal effect was observed. Body saturation of vitamin C has been proposed at plasma level of 1.4mg/100ml. From the results of this study, body saturation maybe reached with a dialy dose of 500 mg in addition to dietary intake. In the preliminary study [3] (data not shown), the time course of blood vitamin level was examined after single administration and daily dministration for one week. This result shows that the profile of plasma vitamin C changes was observed in a similar pattern after administration of a single dose and the 7th day of administration in daily intake. However, the baseline level of plasma vitamin C was increased on the 7th day, as compared with the initial level. This was confirmed again in this study. Urinary excretion increased on the 7th day, reflecting the plasma baseline levels. The above finding indicates that the body must be saturated with vitamin C after repeated intake of the vitamin. Seasonal nutrition survey of the dietary intake of vitamins A, B1, B2, nicotinamide and C was performed in this study. No significant changes in dietary intake of these vitamins were observed throughout the experimnetal period. 2. Vitamin B6 [4]: A similar pattern to vitamin C was observed for vitamin B6. Plasma levels increased during the first 4 to 12 weeks of intake which were follwed by a plateau level during further administration, while urinary excretion of 4-pyridoxic acid, a metabolite of vitamin B6, slightly increased throughout the adminiatration periods. Since the requirement of vitamin B6 depends on protein intake, it was assumed to be about 2 mg/day for a Japanese adult [5]. The doses in this study corresponded to 3.4 times (in group of 9 mg/day) and 6.7 times (in group of 18 mg/day) higher than the level of the vitamin B6 requirement. The body pool of vitamin B6 is thought to saturate as the plasma vitamin B6 level reaches a steady state. Dose-dependent differences

M.MINO et al. 431 were also statistically siginificant in plasma concentrations and urinary excretion among the three groups. From the results of this study, the body pool of vitamin B6 may be increased by increasing doses because of the finding of only a slight increase in urinary excretion of vitamin B6 with continuous intake of the vitamin. In addition, the ordinary doses of vitamin B6 as shown in group of 9 mg/day, will be recommended because general intake of vitamin B6 from the diet, did not seem to satisfy RDA in several reports [6] and there may be many common drugs usually used including contraceptives which contribute to an abnormality of vitamin B6 metabolism. 3. Nicotinamide [4]: Nicotinamide in whole blood shows a different pattern from vitamins C and B6. No significant changes occurred in the whole blood level Fig 2. Changes in plasma nicotinamide levels and urinary excretion of N1- methyl nicotinamide after administration throughout the administration period at both doses. The urinary excretion of N1-methyl nicotinamide, a metabolite of nicotinamide, increased after administration and the value slightly increased throughout the administration period and fell rapidly to the baseline level one week after cessation. A dose response was clearly found in urinary excretion while it was not seen in the whole blood levels. As previously shown in our preliminary study [7], the metabolic turnover rate of nicotinamide was found to be enhanced by repeated intake. The urinary excretion indicates enhancement of nicotimamide metabolism rate during continuous administration. In this study, nicotinamide for metabolism comes from intake of the vitamin itself and metabolically from tryptophan in ingested foos. From the nutritional survey, we can calculate the nicotinamide levels from ingested tryptophan. A correlation between total cotinamide from the preparation and from tryptophan, and excretion levels ni of N1-methyl nicotinamide was then studied. A linear correlation bound to 0 point was observed. From this finding based on excretion of nicotinamide, the levels of ingested nicotinamide used in this experiment shows similar bioavailability at both doses. 4. Vitamin A: Vitamin A is known to cause toxicity such as hypervitaminosis A, in which the plasma retinyl ester level is reported to increase [8]. In RDA research, the vitamin A requirement is known to depend on liver storage of the vitamin [9]. In this study, the plasma retinol level showed no changes with daily intake of 4,000 IU other than dietary intakes. In addition, no peaks corresponding to retinyl ester in HPLC patterns were observed. Therefore, no danger of toxicity was observed during the experimental period indicating that the nutritional status of vitamin A will be enhanced, since liver storage of retinyl ester will probably increase to a non-dangerous level. 5. Vitamin E: Differing from the retinal pattern, plasma alpha-tocopherol

432 Symposium (14) Bioavailability levels increased with daly intake of 20 mg, but not the 10 mg of dl-alpha-tocopheryl acetate, the dose of which was accompanied by slight lowering of the gamma tocopherol level, while no difference was observed between the placebo nistration group andthe group. If 10 mg admi- alpha-tocopherol levels become sufficient, plasma gamma-tpocopherol is known to decrease accompanied with an increase in the plasma alphatocopherol level (10). This indicates that in daily ingestion of 20 mg dl-alpha-tocopheryl acetate the vitamin E status in the body will improve without adverse effects. 6. Side effects and toxicity: Standard clinical screening tests were designed to examine hepatic function, renal sufficiency, the neuromuscular system and hematologic normality. On the basis of this result, it must be concluded that no signs of toxicity were demonstrated in this study. IV. Conclusions: Recently, from the prospective survey of human nutrition Fig 3. Changes in plasma alpha-and gammatocopherol levels after administration. and diseases in the eldery, it has been emphasized that prevention of development of aging diseases including ischemic heart diseases and cancer might be closely related to enhancement of the nutritional status of these vitamins A, C and E [12]. A significant enhancement of the nutritional status of vitamins C, B6 and E was assessed in a 44 weeks administration study using a daily dose of 250-500 mg vitamin C, 9-18 mg vitamin B6 and 20 mg vitamin E. Plasma retinol levels at daily doses of 2,000 and 4,000 IU in addition to dietary intake during the experimental periods did not change and stayed the recommended adequate level. This may assist the goal of enhancement of vitamin A status. The metabolic turnover of nicotinamide was accelerated with a daily doses of 75-150 mg. Neither side effects nor toxicity were documented in all the volunteers including the placebo group on the basis of the finding of the questionnaire and the clinical screening test. References: 1) Murata A, Baba R, Matsuoka M, Otsuka H, Takeuchi T, Itokawa Y.(1989): Plasma level and urinary excretion of vitamin C after oral administration of vitamin C preparations in healthy male adult. Vitamin (Japanese) 63, 1"1-4-1.1q 2) Murata A, Kobayashi T, Matsuoka M, Otska H, Kitagawa M, Mino M, Kimura M, Itokawa Y.(1991): Changes in the pplasma concentration and urinary excretion of vitamin C in healthy male adults during long-term ingestion of a multivitamin preparation. Vitamin (Japanese) 65, in press. 3) Murata A, Baba R, Matsuoka M, Otsuka H, Takeuchi T, Itokawa Y.(1990): Changes in plasma levels and urinary excretion of vitamin C after dialy oral administration of a multivitamin preparation for one week in healthy

M.MINO et al 433 adult males. Vitamin (Japanese) 64, 37-43. 4) Yasuda K, Shimada T, Mino M, Kitagawa M, Itokawa Y, Kimura M, Matsuoka M, Otsuka H.(1991): Changes of blood total vitamin B6 and nicotinamide levels and urinary excretion of their metabolite in normal subjects after longterm administration of a multivitamin preparation. Vitamin (Japanese) 65, in press. 5) Recommended Dieatry Allowances, 10th ed. by National Research Council, National Acad Press, Washington,(1989): Vitamin B6, pp142-149 6) Kant AK, Block G.(1990): Dietary vitamin B-6 intake and food source in the US population: NHANES II, 1976-1980. Am J Clin Nutr 52 707-716 7) Yasuda K, Shomada 5, Itokawa Y, Takeuchi T, Matsuoka M, Otsuka H.(1989): Changes of blood concentrations of vitamin B6 and nicotinic acid and also urinary excretion of their metabolites after administation of three kinds of B-vitmain (B1, B2, B12) or multivitamin preparations. Vitamin (Japanese), 63. 259-268. 8) Olson JA.(1986): Recommended dietary intakes (RDI) of vitamin A in humans. AM J Clin Nutr 45, 704-716. 9) Smith MB, Goodman DS.(1976): Vitamin A transport in human vitamin A toxicity. New Engl J Med 294, 805-808 10) Baker H, Handelman GY, Short S, Machlin LJ, Bhagavan HN, Dratz EA, Frank.(1986): Comparison of plasma alpha-and gamma-tocopherol levels O following chronic oral administration of either all-rac-alpha-tocopheryl acetate or RRR-alpha-tocopheryl acetate in normal adult male subjects. Am J Clin Nutr 43, 382-387 11) Kitagawa M, Mino M.(1989): Effects of elevated d-alpha(rrr)-tocopherol dosage in man. J Nutr Sci Vitaminol 35, 133-142 12) Gey KF, Brubacher GB, Staehelin HB. (1987): Plasma level of antioxidant vitamins in realtion to ischemic heart disease and cancer. Am J Clin Nutr 45, 1368-1377