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Year : 2018  |  Volume : 50  |  Issue : 2  |  Page : 75--83

Pharmacokinetics and bioavailability of chromium malate and its influence on trace metals absorption after oral or intravenous administration

Weiwei Feng1, Qian Li2, Wei Wang2, Ting Zhao3, Yun Feng4, Fang Li4, Guanghua Mao1, Yao Chen1, Yangyang Ding1, Liuqing Yang3, Xiangyang Wu1,  
1 Department of Environmental Engineering, School of the Environment and Safety Engineering, Institute of Environmental Health and Ecological Security, Jiangsu, China
2 Department of Food Science, School of Food and Biological Engineering, Jiangsu University, Jiangsu, China
3 Department of Applied Chemistry, School of Chemistry and Chemical Engineering, Jiangsu University, Jiangsu, China
4 Department of Basic Medicine, School of Medical Science and Laboratory Medicine, Jiangsu University, Jiangsu, China

Correspondence Address:
Prof. Liuqing Yang
School of Chemistry and Chemical Engineering, Jiangsu University, 301 Xuefu Rd, 212013 Zhenjiang, Jiangsu
China

Abstract

OBJECTIVES: In our preliminary study, chromium malate could decrease the blood glucose level in mice with diabetes and exhibits good benefits in treating glycometabolism and adipose metabolization obstacle in rats with type 2 diabetes. This study was aimed at assessing the pharmacokinetics and bioavailability of chromium malate and influence on trace metals absorption in rats. METHODS: BAPP 2.3 pharmacokinetic calculating program (China Pharmaceutical University Medicine Center) was used to calculate the pharmacokinetic parameters. Models of type 2 diabetic mellitus rats were applied to analyzed Ca, Mg, Fe, Cu, and Zn contents. RESULTS: The results showed that mean retention time (MRT) in chromium malate group was significantly prolonged and the area under the curve (AUC) and relative bioavailability of chromium malate (male) group were significant increase compared to chromium picolinate group. The serum Ca, Mg, Fe, Cu, and Zn contents in chromium malate (at doses of 15 and 20 μg Cr/kg bw) groups were significantly increased compared to control group, chromium trichloride group, and chromium picolinate group in type 2 diabetes mellitus rats. CONCLUSIONS: Those results indicated that chromium malate can significantly prolong MRT and increase AUC (male). Moreover, chromium malate is more effective at treating increased serum Ca, Mg, Fe, Cu, and Zn contents compared to chromium trichloride and chromium picolinate.



How to cite this article:
Feng W, Li Q, Wang W, Zhao T, Feng Y, Li F, Mao G, Chen Y, Ding Y, Yang L, Wu X. Pharmacokinetics and bioavailability of chromium malate and its influence on trace metals absorption after oral or intravenous administration.Indian J Pharmacol 2018;50:75-83


How to cite this URL:
Feng W, Li Q, Wang W, Zhao T, Feng Y, Li F, Mao G, Chen Y, Ding Y, Yang L, Wu X. Pharmacokinetics and bioavailability of chromium malate and its influence on trace metals absorption after oral or intravenous administration. Indian J Pharmacol [serial online] 2018 [cited 2021 Dec 2 ];50:75-83
Available from: https://www.ijp-online.com/text.asp?2018/50/2/75/236301


Full Text



 Introduction



Chromium (Cr) is found in natural world primarily as ferrous chromite.[1] Cr occurs in several states at oxidation, ranging from +2 to +6.[2] However, it is unstable except +3 and +6 forms in nature.[3] Studies have shown that Cr 6+ can affect human health, Cr 3+ is a beneficial micronutrient.[4] Currently, the number of people with hyperglycemia and insulin resistance is increasing rapidly in developing and developed countries.[5] Cr 3+ have been widely used as supplements to treat glucose intolerance and insulin resistance.[6],[7] Studies show that Cr 3+ and Cr3+ complex can significantly reduce fasting blood glucose (FBG) level, enhance insulin sensitivity, and regulate lipid metabolism.[8],[9] However, there have studies showed that chromium salt can endanger human health when exposed to the environment. Allergic reaction, ulcers, cancer, cytotoxicity, and intracellular accumulation are adverse effect for chromium salt.[10],[11] Studies showed that the absorption of organic chromium compounds is significantly higher than that of inorganic chromium (chromium acetate and chromium trichloride).[12],[13]

The organic chromium compounds have been widespread used in pharmaceutical raw material, antidiabetic functional food and nutrient supplement.[14],[15] The main organic chromium compounds are chromium picolinate, chromium nicotinate, chromium yeast, chromium methionine, etc. Chromium picolinate is the most commonly applied dietary supplement now. However, studies reported that chromium picolinate had shown the genotoxicity, cytotoxicity, and tumorigenesis which may cause by the ligand (picolinate), and its security has been concerned by the people.[16],[17] Mostafa-Tehrani et al. found that supplementing chromium nicotinate could improve the valuable noncarcass organs, proximal thoracic and pelvic limb in fat-tailed lambs.[18] However, chromium nicotinate has not been used widely, attributed to its poor solubility. Chromium yeast can be obtained from yeast strains and chromium salt under a suitable condition.[19] The application of chromium yeast is restricted because of its lack of stable structure. Therefore, discovering a new and low-toxic organic chromium compounds has become a significant question.

An organic chromium compound-chromium malate was synthesized in our laboratory.[20] The chemical formula of chromium malate is Cr2C12H22O20(or Cr2[C4H4O5]3. 5H2O). Its molecular weight is 590.18 g/mol. The natural ligand formed an organic chromium compound between chromium trichloride and L-malic acid. Chromium malate could improve blood glucose level in diabetic mice. Chromium malate had no oxidative DNA damage and nontoxic in the acute toxicity study and subacute toxicity study.[20] Our recent study found that chromium malate could improve FBG level and insulin resistance in rats with type 2 diabetes and the curative effects of chromium malate are better compared to chromium picolinate and chromium trichloride.[21] The 90-day repeated dose oral toxicity and reproductive toxicity show that chromium malate had no remarkable influence.[22],[23] Therefore, chromium malate has lots of potential at functional foods and nutrient supplement. For now, few studies on pharmacokinetics and bioavailability of the chromium malate had been reported. Chromium malate was used to evaluate pharmacokinetics and bioavailability after oral and intravenous (IV) administration to rats in this study.

 Methods



Ethics statement

The procedures of experiments were according to The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments, Canadian Council on Animal Care guidelines, EC Directive 86/609/EEC for animal experiments, and Jiangsu University Committee on Animal Care and Use. Rats were obtained from the Jiangsu University (the license number SYXK [SU] 2013-0036, certificate number 201804436). It is not a protected and endangered species. The animal tests of our studies abide by the laws and ethical recommendations currently of Jiangsu province, China. The rats were sacrificed after anesthetized by anhydrous diethyl ether.

Materials and chemicals

Chromium trichloride, malic acid, and chromium picolinate were bought in Sinopharm Chemical Reagent Co., Ltd (Shanghai, China). The chromium malate was synthesized in our research group. Nitric and perchloric acid were purchased from Sinopharm Chemical Reagent Co., Ltd. Ultrapure water was used in this experiment.

Animals and diet

Jiangsu University provided the Sprague-Dawley rat (180 ± 10 g) for the studies. The Sprague-Dawley rats were allowed 3 days for acclimation. The Sprague-Dawley rats were consumed distilled water during the whole experiments. The temperatures of the feeding environment is 24°C ± 1°C and its relative humidity is 55%–60%.

Pharmacokinetic analysis

BAPP 2.3 pharmacokinetic calculating program (China Pharmaceutical University Medicine Center) was used to calculate the pharmacokinetic parameters. The methods of AIC and F-test were used to judge the compartment model in this study.[24],[25] The pharmacokinetic analysis was developed according to Vastag et al.[26] reported method. The Sprague-Dawley rats were randomly divided into three groups with 10 rats in each group. The male and female rats were received an oral gavage chromium malate and chromium picolinate after fasting 12 h. The dose of Cr was 20 μg/kg bw. At the same time, rats were administered with chromium malate through caudal vein at same dose of Cr. The Cr levels were used to calculated the dosage of chromium malate and chromium picolinate contents. Blood samples were collected through retro-orbital puncture into heparinized tubes at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3., 4, 5, 6, 8, 10, 12, 14, 16, 24, 36, 48, 60, and 72 h postdoses. The samples of blood were centrifuged at 10,000 g. The time and temperature of centrifuged were 10 min and 4°C, respectively and then the serum was collected.

Cr content analysis

Simultaneous inductively coupled plasma optical emission spectrometry was used to determine the concentration of Cr.[27] The Cr content was measured after wet digestion according to Hashemi [28] and Mickova et al.[29] reported method. 0.1 mL serum was taken out and added in the nitric acid and perchloric acid (1:4, v/v).

Bioavailability analysis

The relative bioavailability (FRB) and absolute bioavailability (FAB) were calculated after serum Cr content was calculated. The FRB and FAB computational formula are as follows:

FRB= AUCchromiummalate× 100%/AUCchromiumpicolinate

FAB= AUCig× 100%/AUCiv

AUC – area under the curve (AUC), ig – intragastric administration, IV injection.

Tissue distribution analysis

After the rats were sacrificed, the hearts, livers, spleens, lung, kidneys, and brain were collected. The method of digested and Cr in tissue distribution was determined method as above described.

Faeces distribution analysis

The rats (male and female) were received an oral gavage chromium malate and chromium picolinate. The dose of Cr was 20 μg/kg bw. Feces samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 6, 12, 24, and 48 h postdoses. Cr in feces distribution was determined after wet digestion. The concentration of Cr was determined using simultaneous inductively coupled plasma optical emission spectrometry.

Calcium, magnesium, iron, copper, and zinc content analysis in type 2 diabetic mellitus rats

Models of type 2 diabetic mellitus (T2DM) rats were inducted using the method of Feng et al.[21] The experimental T2DM rats were randomly divided into three groups. There were 10 rats in a group. The T2DM rats were received an oral gavage dose of 10, 15, 20 μg Cr/kg bw chromium malate and chromium picolinate. The normal saline was administered with oral gavage to T2DM rats as control group. The experimental rats were allowed free access to diet and water after chromium malate and chromium picolinate were administered. The contents of calcium, magnesium, iron, copper, and zinc in standard pellet diet were 6.08, 4.77, 0.27, 0.017, and 0.81 mg/kg, respectively. Blood samples were collected through retro-orbital puncture into heparinized tubes at 0, 1, 2, 3, and 4 weeks. The samples of blood were centrifuged at 10,000 g. The time and temperature of centrifuged were 10 min and 4°C, respectively, and then the serum was collected. The serum was digested by wet digestion according to the method as above described. The contents of Ca, Mg, Fe, Cu, and Zn in T2DM rats were measured by simultaneous inductively coupled plasma optical emission spectrometry method.

Calcium, magnesium, iron, copper, and zinc content analysis in normal rats

The experimental standard deviation rats were randomly divided into three groups. There were 10 rats in a group. The male and female rats were received an oral gavage chromium malate and chromium picolinate. The dose of Cr was 20 μg/kg bw. The normal saline is administered with oral gavage to rats as normal control group. The experimental conditions were same as elemental analysis in T2DM rats. The contents of Ca, Mg, Fe, Cu, and Zn were measured by simultaneous inductively coupled plasma optical emission spectrometry method.

Statistical analysis

Data of above studies were expressed as mean ± standard error of the mean (n = 10). The program SPSS 16.0 (SPSS Inc., Chicago, USA) was used to statistical analyses in this study. The one-way analysis of variance and Tukey's test were used to data analysis and analyze the statistical significance of differences between groups, respectively. P < 0.05, differences of groups were deemed statistically significant.

 Results



Serum concentrations of Cr

Mean serum concentration-time curves of rats in chromium malate and chromium picolinate groups were shown in [Figure 1]. Compared to the commercially available preparations chromium picolinate group, the serum Cr level in chromium malate group was not significant alter [Figure 1]a and [Figure 1]b. The serum concentration of Cr in chromium malate group arrived Tmaxat 1.5 h. At the same time, the serum concentration of Cr in female rats was higher than that of male rats, however, there has no significant change. The serum concentration of Cr in female and male rats was 4.76 ± 0.55 and 4.63 ± 0.37 μg/mL at 1.5 h, respectively. The serum concentration of Cr in chromium malate (female and male, administering injection) group arrived Tmax at 0.5 h when administered intravenously. The time of Tmax was shorter than that of oral gavage chromium malate group. The Cmax of chromium malate (administering injection) group was higher than that of oral gavage in both female and male rats (P > 0.05).{Figure 1}

Compartment model analysis

Pharmacokinetic parameters of rats with compartment model in chromium malate and chromium picolinate groups were shown in [Table 1]. Compared to chromium picolinate group, Cmax of rats supplementing chromium malate has no significant change, and it was slightly lower than that of chromium malate (administering injection) group, however, it was not significantly changed. The Tmax of chromium malate group and chromium picolinate group was identical and it exceeded chromium malate (administering injection) (P < 0.05). In comparison with chromium picolinate and chromium malate (administering injection) groups, no significant difference was observed in the pharmacokinetic parameters (Cmax and Tmax) of chromium malate group in the same gender rats group. The t1/2 of chromium malate group was slightly higher than that of chromium picolinate group. However, in comparison with chromium picolinate and chromium malate (administering injection) groups, there has no significant change in the same gender rats. The mean retention time (MRT) of chromium malate group was significantly higher compared with that of chromium picolinate group in t rats of the same sex (P < 0.05) and it is significantly lower than that of chromium malate (administering injection) group in same-gender rats (P < 0.05). The MRT of chromium malate group in female rats and male rats was 99.63 ± 5.09 and 86.45 ± 4.64, respectively. The chromium malate (Male) has higher AUC0→∞ than that of chromium picolinate (P ≤ 0.05); however, there was no notable increase in female rats and the AUC0→∞ of chromium malate group has no significant change than that of chromium malate (administering injection) group in the same gender rats. The pharmacokinetic parameters (Cmax, Tmax, t1/2, MRT, and AUC0→∞) of chromium malate group have no significant change between female and male rats.{Table 1}

Tissue distribution of Cr

After oral administration by gavage of chromium malate and chromium picolinate for 0.25, 0.50, 0.75, 1, 1.5, 2, 6, 12, 24, and 48 h, the tissue distribution of Cr in chromium malate (male and female) groups and chromium picolinate (male and female) groups in rat organs was different, however, there was no significant changein vivo tissue distribution. The tissue distribution Cr of chromium malate (male and female) groups and chromium picolinate (male and female) groups has no significant change between female and male rats. In comparison with control (male and female) groups, the tissue distribution Cr of chromium malate (male and female) groups still have no notable change. The Cr content of chromium malate group in rat organs is in the following order: spleen > lung > kidney > brain > liver > heart at 12 h. The levels of Cr (male and female) in spleen, lung, kidney, brain, liver, heart were 0.40, 0.52, 0.84, 0.67, 0.61, 0.52 and 0.40, 0.49, 0.78, 0.6, 0.60, 0.50 μg/g at 12 h, respectively.

Feces distribution of Cr

The feces distribution of Cr in chromium malate (male and female) groups and chromium picolinate (male and female) groups after oral gavage of chromium compounds was shown in [Figure 2]. Cr can be discharged from feces in male and female rats. The feces concentration of Cr was increasing tendency following treatment of chromium malate and chromium picolinate. The feces concentration of Cr increased along with the time (in the first 4 h), then decreased. In comparison with chromium picolinate group, the feces concentration of Cr in chromium malate groups has no notable change in the same gender rats. The feces distribution of Cr in chromium malate groups still has no notable change between male and female rats. The Cr concentrations of chromium malate group in male rats and female rats were 0.50 ± 0.06 and 0.47 ± 0.04 μg/g at 5 h, respectively.{Figure 2}

FRB and FAB analysis

According to the compartment model results, FRB of chromium malate group were 105.28% ± 1.62% and 115.73% ± 2.03% in female rats and male rats, respectively. The results illustrated that the FRB of chromium malate group in male rats was significant change compared with that of female rats. The FAB of chromium malate group was 111.80% ± 1.81% and 113.28% ± 1.72% in male rats and female rats, respectively. The FAB of chromium malate group has no significant change between female and male rats.

Serum Ca, Mg, Fe, Cu, and Zn content analysis in type 2 diabetic mellitus rats

The changes in serum Ca, Mg, Fe, Cu, and Zn contents of T2DM rats following treatment of chromium trichloride, chromium picolinate, and chromium malate intragastrically were shown in [Figure 3]. Chromium complexes could increase serum Ca, Mg, Fe, Cu, and Zn contents. In comparison with normal control, chromium trichloride, and chromium picolinate groups, the Ca, Mg, Fe, Cu, and Zn contents of serum in chromium malate (at doses of 15 and 20 μg Cr/kg bw) groups was a notable increase. However, the serum Ca, Mg, Fe, Cu, and Zn contents, which supplementing chromium trichloride and chromium picolinate, has no notable decrease compared to the normal control group. In conclusion, administration of chromium malate can improve trace metals absorption in T2DM rats and chromium malate was more effective at treating increased serum Ca, Mg, Fe, Cu, and Zn contents.{Figure 3}

Serum Ca, Mg, Fe, Cu, and Zn content analysis in normal rats

The changes in serum Ca, Mg, Fe, Cu, and Zn contents of normal male and female rats following treatment of chromium trichloride, chromium picolinate, and chromium malate intragastrically were shown in [Figure 4] and [Figure 5]. After oral gavage of chromium malate for 0, 1, 2, 3, and 4 weeks, it can be observed that serum Ca, Mg, Fe, Cu, and Zn contents were augmented in male rats. However, compared to normal control and chromium picolinate groups, the serum Ca, Mg, Fe, Cu, and Zn contents of chromium malate (male) group have no significant change. The similar results of chromium malate (female) group were obtained in this study [Figure 4]. The serum Ca, Mg, Fe, Cu, and Zn contents in female rats were increased with the increase of administration time. However, compared to normal control group and chromium picolinate group, the Ca, Mg, Fe, Cu, and Zn contents of serum in chromium malate (female) group have no significant change. Those results indicated that chromium malate could not notable promote the absorption of Ca, Mg, Fe, Cu, and Zn in normal male and female rats. Therefore, supplementing chromium malate has no notable effect on Ca, Mg, Fe, Cu, and Zn absorption in normal rats.{Figure 4}{Figure 5}

 Discussion



Studies have suggested that Cr and Cr complex can reduce FBG level in diabetes mellitus. Nowadays, the supplements of Cr are mainly inorganic chromium complex and organic chromium complex. Chromium trichloride is the inorganic chromium complex most commonly utilized as an antidiabetic functional foods or nutrient supplement. However, the disadvantages such as low absorption rate and toxicity have been concerned.[12],[13] Chromium picolinate is the organic chromium complex most frequently applied as antidiabetic functional foods or nutrient supplement. Pattar et al. have found that chromium picolinate can promote glucose uptake, however, its security has been a serious problem.[30] Studies have reported that the ligand (picolinate) of chromium picolinate can cause genotoxicity and cytotoxicity, thus the compound's safety has become the focus of attention.[12],[13]

Chromium malate, one of organic chromium compounds, was been synthesized by our research group. Chromium malate had beneficial effects on the improvement of blood glucose level control in diabetic mice. Chromium malate has no oxidative DNA damage and toxicity in the acute toxicity study and subacute toxicity study.[20] Chromium malate could improve glycometabolism and its related enzyme levels, adipose metabolization obstacle, learning and memory ability, as well as the intestinal flora structure in T2DM rats. The therapeutic effects of chromium malate were better than those of chromium picolinate and chromium trichloride.[21] The results of repeated-dose 90-day oral toxicity and reproductive toxicity showed that supplementation with chromium malate did not cause observed toxicity and did not cause significant effect on glycometabolism and adipose metabolization in normal rats.[22],[23] Chromium malate was used to evaluate pharmacokinetics and bioavailability after oral and IV administration to rats in this study.

The Cmax of chromium malate (administering injection) group was higher than that of oral gavage in both female and male rats. It was attributed to the fact that IV chromium malate was not affected by variable absorption in the gastrointestinal tract or by food intake.[31] The experimental results of this study are consistent with the conventional absorption theory. The tissue distribution of chromium malate (female and male) groups in rat organs was spleen > lung > kidney > brain > liver > heart at 12 h. Kirman et al. have found that chromium level in mouse organs after intraperitoneal administration of chromium trichloride was liver > kidney > pancreas > spleen > testes > lungs > heart > brain.[32] It can be inferred that the new synthesis of chromium malate can reduce the distribution in the liver and kidney when in comparison with chromium trichloride. Chromium malate still has no obvious effect on the absorption of Ca, Mg, Fe, Cu, and Zn in normal rats. Hence, the application of chromium malate has the potential for being as antidiabetic functional foods or nutrient supplement. The results of this study provided a basis for better investigating the pharmacokinetics of chromium malate and evaluating its pharmacological activity.

 Conclusions



Chromium malate can prolong the MRT, increase the AUC and relative bioavailability (male) of Cr in normal rats when in comparison with chromium picolinate group. The Cr content in rat organs was spleen > lung > kidney > brain > liver > heart at 12 h of chromium malate. Administration of chromium malate could improve trace metals absorption in T2DM rats and chromium malate was more effective at treating increased serum Ca, Mg, Fe, Cu, and Zn contents than those of chromium trichloride and chromium picolinate.

Financial support and sponsorship

This work was supported financially by Specialized Research Fund for the Natural Science Foundation of China (31271850), Research Foundation for Advanced Talents of Jiangsu University (15JDG146).

Conflicts of interest

There are no conflicts of interest.

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