Plasma Biotin Research Articles

Variations in plasma biotin and mineral concentrations due to zinc-biotin supplementation in lame Karan Fries cows during peri-parturient period

Nutritional programme of pregnant cows have a significant effect on occurrence of lameness in later lactation. Highly productive lactating cows have much greater needs for minerals and vitamins. Blood biotin and zinc, that are important nutrients in the formation and integrity of the keratinized tissues, often decreases around calving and extra supplementation is recommended, particularly in lame cows during peri-parturient period . The present study was carried out on 40 high yielding lame crossbred KF cows maintained at Livestock Research Centre (LRC), NDRI Karnal, which were distributed into control and three treatment groups and supplemented with 10, 20 and 30 mg/d biotin and 2g of ZnSO<sub>4</sub> during periparturient period. The results of the study suggested that, transition diet with biotin and Zn supplementation significantly increased the concentrations of plasma biotin and Zn levels in supplemental groups compare to control. The overall biotin values were 344.23±11.38, 637.42±24.78, 672.75±29.40 and 709.01±22.77 ng/L and Zn values were 0.40±0.01, 1.12±0.05, 1.22±0.05 and 1.18±0.05 ppm in control, T-1, T-2 and T-3 groups respectively. Thus, by feeding supplemental nutrients (biotin and zinc) lameness can be minimize in high yielding dairy cows during peri-parturient period.

Pregnancy and Lactation Alter Biomarkers of Biotin Metabolism in Women Consuming a Controlled Diet

Background: Biotin functions as a cofactor for several carboxylase enzymes with key roles in metabolism. At present, the dietary requirement for biotin is unknown and intake recommendations are provided as Adequate Intakes (AIs). The biotin AI for adults and pregnant women is 30 μg/d, whereas 35 μg/d is recommended for lactating women. However, pregnant and lactating women may require more biotin to meet the demands of these reproductive states.Objective: The current study sought to quantify the impact of reproductive state on biotin status response to a known dietary intake of biotin.Methods: To achieve this aim, we measured a panel of biotin biomarkers among pregnant (gestational week 27 at study entry; n = 26), lactating (postnatal week 5 at study entry; n = 28), and control (n = 21) women who participated in a 10- to 12-wk feeding study providing 57 μg of dietary biotin/d as part of a mixed diet.Results:Over the course of the study, pregnant women excreted 69% more (vs. control; P < 0.001) 3-hydroxyisovaleric acid (3-HIA), a metabolite that accumulates during the catabolism of leucine when the activity of biotin-dependent methylcrotonyl–coenzyme A carboxylase is impaired. Interestingly, urinary excretion of 3-hydroxyisovaleryl-carnitine (3-HIA-carnitine), a downstream metabolite of 3-HIA, was 27% lower (P = 0.05) among pregnant (vs. control) women, a finding that may arise from carnitine inadequacy during gestation. No differences (P > 0.05) were detected in plasma biotin, urinary biotin, or urinary bisnorbiotin between pregnant and control women. Lactating women excreted 76% more (vs. control; P = 0.001) of the biotin catabolite bisnorbiotin, indicating that lactation accelerates biotin turnover and loss. Notably, with respect to control women, lactating women excreted 23% less (P = 0.04) urinary 3-HIA and 26% less (P = 0.05) urinary 3-HIA-carnitine, suggesting that lactation reduces leucine catabolism and that these metabolites may not be useful indicators of biotin status during lactation.Conclusions: Overall, these data demonstrate significant alterations in markers of biotin metabolism during pregnancy and lactation and suggest that biotin intakes exceeding current recommendations are needed to meet the demands of these reproductive states. This trial was registered at clinicaltrials.gov as NCT01127022.

Plasma and breast milk biotin concentrations decrease in lactating women consuming a dietary biotin intake exceeding current recommendations (827.10)

Biotin is a water‐soluble B vitamin with many key roles in human metabolism. As a cofactor for several carboxylation reactions, biotin is required for gluconeogenesis, fatty acid synthesis, and leucine catabolism. Biotin may also interact with histones to affect genome expression. The dietary requirement for biotin is unknown. Thus, recommendations are provided as Adequate Intakes (AIs). The biotin AI for adults and pregnant women is 30μg/d and for lactating women, 35μg/d. As part of a controlled feeding study, healthy pregnant (n=26, 27wk gestation), lactating (n=28, 5wk postpartum), and control (non‐pregnant, non‐lactating; n=21) women consumed ~60μg dietary biotin/d for 10‐12 weeks. Plasma and breast milk samples were collected and biotin was measured at baseline (wk 0) and study end (wk 10 or 12). Plasma biotin was measured via ELISA kit and breast milk biotin was measured via LCMS. Throughout the study, the response of plasma biotin varied by reproductive group (P = 0.05). Among pregnant (P=0.65) and control (P=0.88) women, plasma biotin did not change from baseline (pregnant: 130ng/L (105, 161); control: 143ng/L (113, 180)) to study end (pregnant: 137ng/L (111, 170); control: 146ng/L (115, 184)). However, among lactating women, plasma biotin decreased (P &lt; 0.01) from baseline (193ng/L (157, 237)) to study end (136ng/L (111, 167)) as did breast milk biotin concentrations (P = 0.02; baseline: 12pM/mL (8.2, 16.5); study end: 7pM/mL (4.8, 9.7)). In addition, plasma and breast milk biotin concentrations were correlated (rho=0.501; P&lt; 0.001). These results indicate that plasma biotin may be a biomarker for breast milk biotin and that lactating women may benefit from a dietary biotin intake that exceeds the study dose of 60μg/d. Data presented as means and 95% confidence intervals.Grant Funding Source: Support:The Hartwell Foundation,The Gerber Foundation,NIH R03 HD065962‐01A1,Shepherd Univ Foundation

Biotin Ameliorates Muscle Cramps of Hemodialysis Patients: A Prospective Trial

Patients with renal failure undergoing hemodialysis often have muscle cramps during and after the dialysis therapy. Muscle cramps are defined as the sudden onset of a prolonged involuntary muscle contraction accompanied with severe pain, resulting in early termination of a HD session and inadequate dialysis. The etiology of the cramps is unknown and effective anti-cramp medicine is not available. We have hypothesized that water-soluble vitamins are deficient in HD patients. Accordingly, we administrated biotin to 14 patients who had frequent muscle cramps during HD sessions. Oral administration of 1 mg/day biotin promptly reduced the onset and the severity of cramps in 12 patients both during and after HD. Then, the plasma biotin levels were measured by an enzyme-linked immunosorbent assay method (ELISA) in HD patients, including 14 patients with cramps and 13 patients without cramps, and 11 healthy volunteers. Plasma biotin levels were elevated in 27 HD patients at baseline compared with healthy volunteers [451 (377 - 649) vs. 224 (148 - 308) ng/l, median (lower-upper quartiles); p < 0.0001]. Unexpectedly, among the 14 cramp patients, the biotin levels were significantly higher in biotin-ineffective 7 patients than biotin-effective 7 patients [1,064 (710 - 1,187) vs. 445 (359 - 476) ng/l; p < 0.001]. Thus, the biotins measured by ELISA may consist of not only intact biotin but also its metabolites that do not function as a vitamin. In conclusion, biotin administration is one choice to relieve HD patients from muscle cramps regardless of their elevated plasma biotin levels.

Inhibition of Intestinal Biotin Absorption by Chronic Alcohol Feeding:Cellular and Molecular Mechanisms

Subramanya SB, Subramanian VS, Kumar JS, Hoiness R, Said HM. Inhibition of intestinal biotin absorption by chronic alcohol feeding: cellular and molecular mechanisms. Am J Physiol Gastrointest Liver Physiol 300: G494–G501, 2011. First published December 9, 2010; doi:10.1152/ajpgi.00465.2010.—The water-soluble vitamin biotin is essential for normal cellular functions and its deficiency leads to a variety of clinical abnormalities. Mammals obtain biotin from exogenous sources via intestinal absorption, a process mediated by the sodium-dependent multivitamin transporter (SMVT). Chronic alcohol use in humans is associated with a significant reduction in plasma biotin levels, and animal studies have shown inhibition in intestinal biotin absorption by chronic alcohol feeding. Little, however, is known about the cellular and molecular mechanisms involved in the inhibition in intestinal biotin transport by chronic alcohol use. These mechanisms were investigated in this study by using rats and transgenic mice carrying the human full-length SLC5A6 5=-regulatory region chronically fed alcohol liquid diets; human intestinal epithelial Caco-2 cells chronically exposed to alcohol were also used as models. The results showed chronic alcohol feeding of rats to lead to a significant inhibition in carrier-mediated biotin transport events across jejunal brush border and basolateral membrane domains. This inhibition was associated with a significant reduction in level of expression of the SMVT protein, mRNA, and heterogenous nuclear RNA. Chronic alcohol feeding also inhibited carrier-mediated biotin uptake in rat colon. Studies with transgenic mice confirmed the above findings and further showed chronic alcohol feeding significantly inhibited the activity of SLC5A6 5=-regulatory region. Finally, chronic exposure of Caco-2 cells to alcohol led to a significant decrease in the activity of both promoters P1 and P2 of the human SLC5A6 gene. These studies identify for the first time the cellular and molecular parameters of the intestinal biotin absorptive processes that are affected by chronic alcohol feeding.

Inhibition of intestinal biotin absorption by chronic alcohol feeding: cellular and molecular mechanisms.

The water-soluble vitamin biotin is essential for normal cellular functions and its deficiency leads to a variety of clinical abnormalities. Mammals obtain biotin from exogenous sources via intestinal absorption, a process mediated by the sodium-dependent multivitamin transporter (SMVT). Chronic alcohol use in humans is associated with a significant reduction in plasma biotin levels, and animal studies have shown inhibition in intestinal biotin absorption by chronic alcohol feeding. Little, however, is known about the cellular and molecular mechanisms involved in the inhibition in intestinal biotin transport by chronic alcohol use. These mechanisms were investigated in this study by using rats and transgenic mice carrying the human full-length SLC5A6 5'-regulatory region chronically fed alcohol liquid diets; human intestinal epithelial Caco-2 cells chronically exposed to alcohol were also used as models. The results showed chronic alcohol feeding of rats to lead to a significant inhibition in carrier-mediated biotin transport events across jejunal brush border and basolateral membrane domains. This inhibition was associated with a significant reduction in level of expression of the SMVT protein, mRNA, and heterogenous nuclear RNA. Chronic alcohol feeding also inhibited carrier-mediated biotin uptake in rat colon. Studies with transgenic mice confirmed the above findings and further showed chronic alcohol feeding significantly inhibited the activity of SLC5A6 5'-regulatory region. Finally, chronic exposure of Caco-2 cells to alcohol led to a significant decrease in the activity of both promoters P1 and P2 of the human SLC5A6 gene. These studies identify for the first time the cellular and molecular parameters of the intestinal biotin absorptive processes that are affected by chronic alcohol feeding.

Biotin and biotinidase deficiency

Biotin is a water-soluble vitamin that serves as an essential coenzyme for five carboxylases in mammals. Biotin-dependent carboxylases catalyze the fixation of bicarbonate in organic acids and play crucial roles in the metabolism of fatty acids, amino acids and glucose. Carboxylase activities decrease substantially in response to biotin deficiency. Biotin is also covalently attached to histones; biotinylated histones are enriched in repeat regions in the human genome and appear to play a role in transcriptional repression of genes and genome stability. Biotin deficiency may be caused by insufficient dietary uptake of biotin, drug–vitamin interactions and, perhaps, by increased biotin catabolism during pregnancy and in smokers. Biotin deficiency can also be precipitated by decreased activities of the following proteins that play critical roles in biotin homeostasis: the vitamin transporters sodium-dependent multivitamin transporter and monocarboxylate transporter 1, which mediate biotin transport in the intestine, liver and peripheral tissues, and renal reabsorption; holocarboxylase synthetase, which mediates the binding of biotin to carboxylases and histones; and biotinidase, which plays a central role in the intestinal absorption of biotin, the transport of biotin in plasma and the regulation of histone biotinylation. Symptoms of biotin deficiency include seizures, hypotonia, ataxia, dermatitis, hair loss, mental retardation, ketolactic acidosis, organic aciduria and also fetal malformations. This review focuses on the deficiencies of both biotin and biotinidase, and the medical management of such cases.

Effects of Dietary Supplements of Folic Acid and Vitamin B12 on Metabolism of Dairy Cows in Early Lactation

The present experiment was undertaken to determine the effects of dietary supplements of folic acid and vitamin B12 given from 3 wk before to 8 wk after calving on lactational performance and metabolism of 24 multiparous Holstein cows assigned to 6 blocks of 4 cows each according to their previous milk production. Supplementary folic acid at 0 or 2.6 g/d and vitamin B12 at 0 or 0.5 g/d were used in a 2×2 factorial arrangement. Supplementary folic acid increased milk production from 38.0±0.9 to 41.4±1.0 kg/d and milk crude protein yield from 1.17±0.02 to 1.25±0.03 kg/d. It also increased plasma Gly, Ser, Thr, and total sulfur AA, decreased Asp, and tended to increase plasma Met. Supplementary B12 decreased milk urea N, plasma Ile, and Leu and tended to decrease Val but increased homocysteine, Cys, and total sulfur AA. Liver concentration of phospholipids was higher in cows fed supplementary B12. Plasma and liver concentrations of folates and B12 were increased by their respective supplements, but the increase in plasma folates and plasma and liver B12 was smaller for cows fed the 2 vitamins together. In cows fed folic acid supplements, supplementary B12 increased plasma glucose and alanine, tended to decrease plasma biotin, and decreased Km of the methylmalonyl-coenzyme A mutase in hepatic tissues following addition of deoxyadenosylcobalamin, whereas it had no effect when cows were not fed folic acid supplements. There was no treatment effect on plasma nonesterified fatty acids as well as specific activity and gene expression of Met synthase and methylmalonyl-coenzyme A mutase in the liver. Ingestion of folic acid supplements by cows fed no supplementary B12 increased total lipid and triacylglycerols in liver, whereas these supplements had no effect in cows supplemented with B12. The increases in milk and milk protein yields due to folic acid supplements did not seem to be dependent on the vitamin B12 supply. However, when vitamin B12 was given in combination with folic acid, utilization of the 2 vitamins seems to be increased, probably more so in extrahepatic tissues. Metabolic efficiency seems also to be improved as suggested by similar lactational performance and dry matter intake for cows fed supplementary folic acid but increased plasma glucose and decreased hepatic lipids in cows fed folic acid and vitamin B12 together.

Impact of B-vitamin supply on major metabolic pathways of lactating dairy cows

Knowledge of the major nutrient requirements of dairy cows has increased substantially during the past decades. Little is known, however, about the importance of the roles played by B vitamins. Since most of those vitamins act as essential cofactors in energy, protein and lipid metabolism, it is likely that as milk yield increases, the demand for these cofactors also increases. The supply of B vitamins from dietary sources and synthesis by the ruminal microflora is generally sufficient to avoid deficiency symptoms, but could be insufficient for optimizing metabolic efficiency, production, composition and the nutritional quality of milk in high-producing dairy cows. Results from recent experiments show how the supply of three B vitamins — folic acid, biotin and vitamin B12 — affects major metabolic pathways. Supplementary biotin has frequently been reported to increase milk yield but has a limited effect on milk composition. Folic acid supplements have been found to increase milk and milk protein yields in multiparous cows without affecting dry matter intake when vitamin B12 supply was adequate. An insufficient vitamin B12 supply blocked those effects but they can be restored through vitamin B12 supplementation. Supplemental vitamin B12 and biotin increased milk and milk protein yields without changing dry matter intake. Vitamin B12 utilization by tissues increased in cows fed supplementary folic acid simultaneously; plasma glucose also increased in these cows but plasma biotin decreased. From these findings, it appears that, in high-producing dairy cows, especially in early lactation, the strong competition for nutrients that occurs between gluconeogenesis, methylneogenesis and protein synthesis increases the amount of folic acid, vitamin B12 and biotin required to maintain metabolic efficiency, especially when the nutrient supply is limited. These observations emphasize the need to review the paradigm according to which B-vitamin supply by ruminal microflora cannot be limiting in dairy cow. Key words: Dairy cow, B vitamins, folic acid, vitamin B12, biotin, lactation, metabolism

Experimental Study of Fatigue Provoked by Biotin Deficiency in Mice

We investigated the relationships among behavioral parameters, forced-swimming test parameters, and plasma and organ biotin concentrations in biotin-deficient mice. Male ddY mice were divided into four groups: early biotin deficiency group (ED group; biotin-free diet for three weeks), progressive biotin-deficiency group (PD group; biotin-free diet for seven weeks), and two age-matched control groups. The dermatological symptoms of frank biotin deficiency were observed in most mice in the PD groups (72.3%) but in only 27% of ED group mice. The liver biotin level was greatly decreased in ED and PD groups, and the plasma biotin level was also significantly decreased in the PD group, but the biotin levels were quite stable in muscle and brain. There were significant decreases in swimming time in ED and PD groups and in struggling behavior in the PD group, suggesting that biotin-deficient mice become depressed and/or fatigued without biotin deficiency being apparent in brain and muscle. One single-injection biotin administration led to a prompt recovery in swimming time. Biochemical data revealed a decrease in liver glucokinase activity and an increase in ketone bodies in both liver and plasma in biotin-deficient mice. In addition, simultaneous biotin deficiency and forced walking synergistically provoked significant increases in total ketone bodies in both plasma and liver. These results suggest that depression and/or fatigue are induced in mice by biotin deficiency.

Effects of Biotin Supplementation on Peripartum Performance and Metabolites of Holstein Cows

Fifty-two multiparous Holstein cows were randomly assigned to receive 0 or 20mg of biotin/d starting at an average of 16 d prepartum and then switched to 0 or 30mg of biotin/d from calving through 70 d postpartum to determine whether supplemental biotin would affect cow performance, hepatic lipidosis, and plasma metabolites. Mean concentration of biotin in plasma sampled weekly was greater in cows fed biotin (4.3 vs. 9.4nmol/L). Postpartum dry matter intake as a percentage of body weight (3.9% vs. 4.0%), milk production (35.8 vs. 34.8kg/d), and milk fat concentrations (3.59% vs. 3.69%) were similar between treatment groups. Milk from biotin-supplemented cows tended to have a greater concentration of protein (2.73% vs. 2.83%). Concentrations of plasma nonesterified fatty acids were lower at wk 2 (652 vs. 413μEq/mL) and 4 (381 vs. 196μEq/mL) postpartum in cows fed supplemental biotin. However, mean plasma concentrations of β-hydroxybutyric acid were not affected by biotin supplementation. Mean concentration of plasma glucose was greater for lactating cows fed supplemental biotin (63.4 vs. 66.6mg/dL). Biopsies of liver were taken at 2, 16, and 30 d postpartum. The triacylglycerol concentration in liver (wet basis) tended to decrease at a faster rate after d 2 postpartum with biotin supplementation compared with control cows. The potential mechanisms that link improved glucose status and decreased lipid mobilization in cows supplemented with biotin warrant further investigation.

Balance and serum concentration of biotin in sheep fed alfalfa meal-based diets with increasing level of concentrate.

The objective of this study was to test the hypothesis that serum biotin concentration and biotin balance (consumed - [urinary output + fecal output]) measured as total avidin-binding substances (biotin + biotin metabolites) are responsive to changes in the proportions of dietary alfalfa meal and concentrate fed to sheep. Eight sheep (initial BW = 40 kg) consumed a pelleted alfalfa meal-based diet that had 95:5, 48:52, 23:77, or 9:91% alfalfa meal:concentrate ratios (DM basis) in a replicated 4 x 4 Latin square design with 20-d periods (10 d of acclimation, 7 d of adaptation, and a 3-d collection period with jugular blood drawn on the last day). Replacing alfalfa meal with concentrate in the pelleted diets decreased dietary concentrations of biotin proportionally. As the percentage of alfalfa meal in the diet decreased, there was a linear decrease in daily DM intake (1,128 to 901 g of DMI/d; P < 0.01), with a linear (P < 0.01) and quadratic (P < 0.01) increase in the apparent total-tract DM digestibility of diets (51.0 to 80.0%). The biotin consumed decreased with alfalfa meal proportion in the diet (linear, P < 0.01). Both fecal biotin concentration (linear, P < 0.01) and fecal biotin output (quadratic, P < 0.05) increased, reaching peaks at 23% alfalfa meal. Fecal biotin output was not correlated with biotin intake, DMI, or intake of digestible DM. Mean urinary output, urinary biotin concentration, urinary biotin output, and serum biotin concentration were not affected by treatments. Means of biotin balance were negative and revealed the same trends among treatments as did fecal output. Biotin balance was a quadratic (P < 0.05) function of decreasing alfalfa meal in the diet, with more negative values at the alfalfa meal:concentrate ratio of 23:77. Results suggest that the greatest synthesis of biotin in the total digestive tract occurs with diets of either 52 or 77% concentrate for sheep; however, research addressing the significance of biotin metabolites on biotin balance and plasma biotin pool is needed.

A sensitive and practical competitive radioassay for plasma biotin.

Biotin is a water-soluble vitamin which plays an important biochemical role in a variety of carboxylase-mediated metabolic reactions. Determination of biotin status for the diagnosis of biotin deficiency is crucial. We describe a solid-phase protein-binding assay involving [(125)I]iodostreptavidin as a tracer for the determination of biotin in plasma. The assay was conducted in one step by incubation of a fixed amount of [(125)I]iodostreptavidin as binding reagent with varying amounts of biotin, diluted in biotin-free plasma (standard curve) or unknown samples in tubes previously coated with biotin linked to goat antirabbit IgG. Increasing amounts of biotin in the standard or unknown samples in tubes previously coated with biotin occupy more sites on iodostreptavidin, resulting in fewer counts bound to tubes. The effects of the incubation time and temperature on the competitive binding of biotin with iodostreptavidin were tested. The detection limit of the plasma assay for biotin was 100 pmol/L. Only 100 microL of plasma were necessary for the assay, which was performed within 6 h. The dilutions of plasma and synthetic biotin gave a parallel response. Plasma biotin levels ranged from 0.49 to 1.33 nmol/L (mean 0.76 nmol/L) in healthy subjects. The intra and inter-assay coefficients of variation were 3.5% and 10%, respectively, at a concentration of 0.27 nmol/L. This assay was suitable for the direct measurement of biotin in human plasma and was robust and sensitive enough for screening for biotin deficiency.

Dietary Biotin Intake Modulates the Pool of Free and Protein-Bound Biotin in Rat Liver

The current studies were undertaken to analyze the relationships among dietary biotin intake, hepatic free biotin and hepatic protein-bound biotin in rats. The biotin status of rats was manipulated through dietary intervention to model moderate biotin deficiency, adequacy, supplementation and pharmacologic biotin supplementation (0, 0.06, 0.6 and 100 mg/kg, respectively). Urinary biotin excretion was directly related to biotin intake, but no difference between biotin-adequate and biotin-supplemented rats was detected. In contrast, plasma biotin was directly and significantly regulated by biotin intake at every intake level. A hepatic free biotin pool was directly demonstrated in these studies, and like plasma, its size was directly related to dietary biotin intake. The relationship between dietary biotin intake and protein-bound biotin was also analyzed. Moderate biotin deficiency markedly decreased the abundance of each biotinylated polypeptide in rat liver. Biotin supplementation did not significantly elevate the abundance of biotinylated pyruvate, propionyl CoA, methylcrotonyl CoA or acetyl CoA carboxylase 1. The abundance of biotinylated acetyl CoA carboxylase 2, however, was significantly higher in biotin-supplemented rats. Pharmacologic biotin intake significantly reduced the abundance of biotinylated propionyl CoA and methylcrotonyl CoA carboxylase. These results indicate the following: 1) moderate biotin deficiency reduces free and protein bound biotin; 2) biotin intakes in rats that mimic the currently recommended daily value (DV) do not result in full protein biotinylation; and 3) pharmacologic supplementation may reduce the abundance of functional carboxylases.

The Clearance and Metabolism of Biotin Administered Intravenously to Pigs in Tracer and Physiologic Amounts Is Much More Rapid than Previously Appreciated

Understanding of biotin pharmacokinetics and regulation of metabolism is essential for the determination of the biotin requirement for humans. Using Landrace-Cambrough pigs as a model, we initially demonstrated that biotin binding to protein accounts for only a small percentage of the total biotin in plasma. A physiologic amount of [14C]biotin was administered intravenously to three pigs; nine blood samples were collected over 48 h. Plasma concentrations of 14C-labeled metabolites were negligible for the first 2 h after biotin infusion. Disappearance curves of total 14C and of [14C]biotin were similar; both fit a triexponential function consistent with a three-compartment, open model. To characterize the rapid early phase of disappearance more precisely, a physiologic amount of [14C]biotin was administered intravenously to five pigs; eight blood samples were collected over the first hour and 16 total samples over 48 h. Again a triexponential function provided an excellent fit. The mean half-life values (+/- 1 SD) for the three phases were 0.11 +/- 0.07, 1.43 +/- 0.42 and 22 +/- 4 h. The [14C]biotin accumulated primarily in the liver, kidney and muscle. When administered intravenously at tracer doses to three pigs, [3H]biotin exhibited similar early pharmacokinetics; however, substantial quantities of a 3H-labeled metabolite appeared after 1 h. These studies provide evidence that egress of biotin from plasma is more rapid than previously appreciated. The slower second and third phases may represent transport into the cytosol, biotransformation into intermediates and covalent binding to intracellular proteins. Similar pharmacokinetics are likely to be seen in humans.

Effects of Supplemental Dietary Biotin on Performance of Holstein Cows During Early Lactation

This study determined the effects of supplemental dietary biotin (0, 10, or 20 mg/d) on performance of Holstein cows (n=45; 18 primiparous and 27 multiparous). Treatments started at 14 d prepartum and continued until 100 d in milk (DIM). Blood samples were taken at 14 d prepartum, and blood and milk samples were taken at calving, and 30, 60, and 100 DIM. Dry matter intake during lactation was not different across treatments (19.7 kg/d). Milk production linearly increased with biotin supplementation (36.9, 37.8, and 39.7 kg/d for 0, 10, and 20 mg/d of supplemental biotin, respectively). Biotin supplementation did not affect milk fat and true protein percentages or fat yield but linearly increased true protein yield. Supplemental biotin increased concentrations of biotin in plasma and milk at all time points. Concentrations of biotin in plasma and milk (colostrum) at calving were higher than at other time points for cows fed supplemental biotin. In an ancillary experiment, plasma biotin concentrations were not as high when cows were fed 20 mg/d of supplemental biotin for 14 d during the middle of their dry period as when cows were fed 20 mg/d of biotin for the last 14 d of gestation. This suggests that events associated with parturition altered plasma biotin concentrations. Plasma concentrations of glucose, insulin, nonesterified fatty acids, and molar proportions of ruminal volatile fatty acids were not affected by biotin supplementation. Biotin supplementation had no effect on change in body weight or condition score. Supplemental biotin linearly increased milk and protein yields, however, the mode of action that caused these increases was not determined.

Biotin Plasma Levels of theHuman Fetus

Biotin is an important vitamin for cellular function and growth and, therefore, essential for fetal development. The fetus is exclusively dependent on maternal biotin supply. Since biotin is not produced within the body, maternal biotin levels depend on dietary intake. In order to investigate the biotin status of the human fetus, we measured the plasma biotin levels in 15 pregnant women and their fetuses who underwent amniocentesis and fetal blood sampling at 18–24 weeks of gestation for prenatal diagnosis of thalassemia. Maternal biotin was found to be 131 ± (SD) 102 ng/l and fetal biotin 784 ± 327 ng/l (p < 0.0001). Our findings are indicative of an active transport mechanism of biotin through the placenta in favor of the fetus.

Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy.

In subjects undergoing long-term therapy with carbamazepine and/or phenytoin, reduced plasma concentrations of biotin have been reported. However, the diagnostic value of plasma biotin is unclear, in part because of the presence of significant plasma concentrations of biotin metabolites. Pathologic organic aciduria has also been reported with long-term anticonvulsant therapy, suggesting biotin deficiency, but no mechanism leading to deficiency has yet been determined. In the current study, we sought to determine whether biotin catabolism was accelerated in children receiving long-term treatment with certain anticonvulsants and to assess biotin status as judged by urinary excretion of biotin and 3-hydroxyisovaleric acid, an organic acid that is an indicator of deficiency of a biotin-dependent enzyme. Seven children treated with carbamazepine and/or phenytoin and six treated with phenobarbital provided untimed urine samples. Sixteen healthy children receiving no anticonvulsants served as controls. Biotin and biotin metabolites were determined by high-performance liquid chromatography/avidin-binding assay. Urinary excretion of 3-hydroxyisovaleric acid was determined using gas chromatography/mass spectrometry. Bisnorbiotin excretion was increased significantly in the carbamazepine/phenytoin group and in the phenobarbital group. Biotin sulfoxide excretion was significantly increased in the carbamazepine/phenytoin group but not in the phenobarbital group. 3-Hydroxyisovaleric acid excretion was increased significantly in the carbamazepine/phenytoin group. However, only one child (carbamazepine/phenytoin group) had a decreased urinary excretion of biotin. These data provide evidence that long-term administration of some anticonvulsants can accelerate biotin catabolism, but the indicators of biotin status conflict.

Biotin supplementation affects lymphocyte carboxylases and plasma biotin in severe protein-energy malnutrition

We studied the effect of a supplement of biotin (10 mg/d) or a placebo under double-blind conditions on plasma biotin concentrations and lymphocyte propionyl CoA carboxylase (PCC) and pyruvate carboxylase (PC) in 22 children with severe protein-energy malnutrition (PEM) (5 with kwashiorkor, 10 with marasmus, and 7 "sugar babies"). There were significant differences between the malnourished and control subjects only for PCC, although not among the three PEM types. Six of the patients had both PC and PCC activities below the lowest of the normal control subjects; there was no correlation between biotin concentrations and carboxylase activities in individual patients. In response to biotin supplementation, the greatest change in lymphocyte carboxylase activities was detected in patients who had abnormally decreased initial carboxylase activities, but the response was not related to initial plasma biotin concentration. These results indicate that these enzyme deficiencies are the result of a nutritionally determined biotin deficiency, that carboxylases and especially PCC are better indicators of the biotin status in individual patients than is the plasma biotin concentration, and that in some malnourished patients biotin deficiency may be rate-limiting in their nutritional homeostasis.

Distribution of biotin in human plasma: most of the biotin is not bound to protein

Estimates of the plasma concentration of biotin differ considerably. Variation in detectability of biotin bound covalently to protein is one potential source of disagreement. In this study we determined the amount of biotin covalently bound to plasma protein. First, greater than 99% of free and reversibly bound biotin was removed by dialysis; then greater than 90% of covalently bound biotin was released by acid hydrolysis. For plasma samples from 11 normal adults, the ratio of covalently bound biotin to free biotin was 0.15 +/- 0.09 (mean +/- SD). Taking into account the additional biotin that is reversibly bound to protein, this study provides evidence that approximately 12% of total biotin in plasma is covalently bound, 7% is reversibly bound, and 81% is free. We conclude that covalently bound biotin cannot account for the reported sixfold increase in biotin detected after acid hydrolysis. We speculate that the reported increase was an artifact caused by substances produced during acid hydrolysis of plasma.