Calcium D-Glucarate Technical Information

Calcium D-Glucarate

Calcium D-glucarate is a natural glucose metabolite which is an effective inhibitor of β-glucuronidase – an enzyme which deconjugates bound toxins and other metabolic waste products. Glucuronidation is a key phase II process that assists in the detoxification of oestrogen and xeno-oestrogen compounds from the environment. By preventing deconjugation of products of glucuronidation, calcium D-glucarate promotes a net increase in phase II detoxification and is indicated in toxicity-associated conditions, especially those involving excessive oestrogen activity.

HERBS AND NUTRIENTS THAT MAY ASSIST

Calcium D-glucarate

CLINICAL APPLICATIONS

KEY ACTIONS:

  • Inhibits β-glucuronidase and increases net phase II glucuronidation
  • Decreases oestrogen
  • Anticarcinogenic
  • Improves lipid and bile metabolism
  • Anti-inflammatory
  • Antioxidant

KEY APPLICATIONS:

  • Oestrogen/xeno-oestrogen dependent conditions
o Endometriosis
o Fibroids
o Breast cancer
  • Cancer, especially breast and prostate

May also be considered for:

  • Gallstones
  • Dyslipidaemia

DOSES

  • Oestrogen/xeno-oestrogen detoxification: 1500-3000 mg daily
  • Cancer: 1500-3000 mg daily
  • Gallstones: 1500-3000 mg daily
  • Dyslipidaemia: 1500-3000 mg daily

BACKGROUND TECHNICAL INFORMATION

Glucuronidation

Glucuronidation is an important phase II detoxification process which attaches glucuronic acid to a toxin for excretion. Glucuronic acid serves as conjugation compound for the detoxification of a wide variety of endogenous and exogenous substrates, including sex hormones and toxins.1,2 In glucuronidation, the enzyme uridine 5'-diphospho-(UDP)-glucuronosyltransferase (UDG) attaches the water-soluble glucuronic acid to the more fat-soluble substrate, creating a conjugate compound which is now water-soluble for elimination.

β-glucuronidase

The enzyme β-glucuronidase reverses the process of glucuronidation; deconjugating the glucuronic acid from the toxin and ‘re-activating’ it, as it is no longer bound. The amount of a toxin that is eliminated is believed to be largely determined by the balance of conjugation versus deconjugation (Figure 1).

Calcium D-Glucarate Figure 1 Glucuronidation and deglucuronidation of toxins - HealthMasters

Figure 1. Glucuronidation and deglucuronidation of toxins.

The net amount of toxin detoxified is determined by the balance between conjugation via uridine 5'-diphospho—glucuronosyltransferase (UDG) and deconjugation from β-glucuronidase (BG).

Humans synthesise β-glucuronidase and it has been detected in many tissues including liver, kidney, spleen, testes, lung, gastrointestinal tract, and in cancerous and inflamed tissue. Additionally, a dysbiotic gastrointestinal microbiome produces high levels of β-glucuronidase, which can act identically to human β-glucuronidase, by deconjugating glucuronidated substances.4

Essentially, almost any tissue and body compartment can deconjugate glucuronidated compounds and restore their bioactivity via β-glucuronidase. 
β-glucuronidase is believed to have a constitutive role in degrading glycosaminoglycans for tissue remodelling. However, as is the case with many inflammation-induced mediators, down-regulating excessive levels is a useful short or long term strategy in the control of disease, with little risk of compromising normal physiology. Elevated levels of β-glucuronidase have been found in various pathologies and inflammatory disorders, with elevated levels linked to cancer risk.5,6,7 β-glucuronidase levels are naturally suppressed by compounds found in a healthy diet (described below); indicating that control of β-glucuronidase activity can be considered an normal and safe strategy to restore homeostasis in situations of dysbiosis and inflammation.

INGREDIENTS

Calcium D-glucarate is glucose-like compound, which upon ingestion is metabolised in the stomach to form D-glucaric acid. D-glucaric acid can be obtained from the diet from plant foods, most notably in grapefruits, apples, oranges and cruciferous vegetables. A diet high in fruits and vegetables is estimated to provide around 200 mg/day of D-glucaric acid.8 Additionally, humans can synthesis small amounts of D-glucaric acid in the liver from glucose.9

Calcium D-glucarate, and the resulting D-glucaric acid, are further metabolised to create D-glucaro-1,4-lactone (1,4-GL), which has been shown to be the active form of supplemental calcium D-glucarate (Figure 2).10

Calcium D-Glucarate Figure 2 The metabolism of calcium D-glucarate - HealthMastersFigure 2. The metabolism of calcium D-glucarate to the bioactive compound D-glucaro-1,4-lactone.

1,4-GL acts to attenuate the deconjugation of products of glucuronidation by inhibiting β-glucuronidase and thus allow the toxin to be eliminated successfully.11

ACTIONS

INHIBITS β-GLUCURONIDASE AND INCREASES NET PHASE II GLUCURONIDATION

The key mechanism of action of calcium D-glucarate is inhibition of β-glucuronidase. Calcium D-glucarate therefore has the potential to mitigate deconjugation of glucuronidated compounds, such as oestrogen, and promote safe excretion of the conjugated substance.12,13,14,15

The ability of calcium D-glucarate to inhibit β-glucuronidase was first demonstrated over sixty years ago and numerous studies since have confirmed its ability. For example, feeding rodents a single dose of calcium D-glucarate results in significant inhibition in β-glucuronidase in several sites, including serum, liver, lung and intestine (Figure 3).16 The activity of β-glucuronidase has been found to be elevated in many disease states, including numerous types of cancers, diabetes, heart disease, rheumatoid arthritis, liver pathology, cholelithiasis, inflammation, jaundice, tuberculosis, and sarcoidosis.17,18

Calcium D-Glucarate Figure 3 The effect of calcium D-glucarate - HealthMasters
Figure 3. The effect of calcium D-glucarate (CDC) on β-glucuronidase activity in several tissues.19
* p<0.05 compared to control

DECREASES OESTROGEN

Inhibition of β-glucuronidase with calcium D-glucarate can allow more substrate to remain conjugated, with a net change of increasing phase II detoxification.20 For example, rats showed a 23% reduction in serum oestradiol and a 55% reduction in oestrone levels when fed calcium D-glucarate (Figure 4).21

Calcium D-Glucarate Figure 4 Percentage reduction in serum oestradiol - HealthMasters

Figure 4. Percentage reduction in serum oestradiol and urinary oestrone in rats feed calcium D-glucurate. 22

ANTICARCINOGENIC

Inhibiting β-glucuronidase is considered to be a key mechanism in calcium D-glucaric acid’s anticarcinogenic effect. It is suggested that calcium D-glucarate’s action is largely due to its ability to detoxify hormones and exogenous toxins that are linked to carcinogenesis. Environmental carcinogens and endogenous oestrogens can cause DNA mutations and promote tumourigenesis; therefore promoting of glucuronidation of these toxins can reduce the carcinogenic load.23 Additionally, tumours contain high levels of β-glucuronidase which is linked to inflammation and subsequent metastasis, with researchers suggesting inhibition of β-glucuronidation may attenuate inflammation and metastasis.24,25

Outside of inhibiting β-glucuronidase, calcium D-glucarate has several other anti-carcinogenic actions. It inhibits protein kinase-C activity and induces transforming growth factor β, which can result in an increase in cellular differentiation and regulate progression through the cell cycle. Calcium D-glucarate has also been found to synergistically interact with retinoids and powerfully inhibit carcinogenesis in animal models.26

IMPROVES LIPID AND BILE METABOLISM

Evidence shows that calcium D-glucarate administration reduces serum cholesterol levels, with research suggesting that it may be modulating steroidogenesis.27 Additional research suggests that calcium D-glucarate is useful for promoting healthy bile flow. β-glucuronidase in the biliary tract can deconguate bile salts, such as bilirubin, which can allow gallstones to precipitate.28 Mice receiving 1,4 GL showed a decrease in the biliary β- glucuronidase activity, indicating a reduction of bile deconjugation.29

ANTI-INFLAMMATORY

Recent evidence shows that 1,4-GL has an anti-inflammatory effect independent of its β-glucuronidase inhibiting action. 1,4-GL was found to inhibit key intercellular inflammatory mediators such as protein kinase C and nuclear factor kappa B.30

ANTIOXIDANT

Several recent studies have demonstrated that calcium D-glucarate has a potent antioxidant activity, also independent of inhibition of β-glucuronidase. Saluk-Juszczak et al found that 1,4-GL had a significant antioxidant activity against oxidative damage to lipids and proteins of platelets, induced by very strong oxidants, such as reactive nitrogen species and reactive oxygen species.31 Similarly, Rashid et al found 1,4- GL reduced oxidative stress and improved glutathione status in mice administered the diabetes-inducing compound alloxan.32

APPLICATIONS

OESTROGEN / XENO-OESTROGEN DEPENDENT CONDITIONS

A number of female reproductive conditions are linked to elevated systemic and/or tissue levels and/or elevated environmental chemicals (“xeno-oestrogens”) (Table 1). The high levels of oestrogens and xeno-oestrogens are thought to contribute to the pathology, through such mechanisms as increasing inflammation, promoting undifferentiated growth and causing DNA damage. One strategy to treat oestrogen/xeno-oestrogen dominant conditions is to promote detoxification and subsequently reduce body levels of these compounds.

The use of calcium D-glucarate can be viewed as one tool for reducing oestrogen/xeno-oestrogen levels by promoting net glucuronidation.

Table 1. Female reproductive conditions associated with oestrogen and/or xeno-oestrogen excess. 33,34,35,36,37,38,39

 Elevated tissue or serum concentration of oestrogen found in: Elevated xeno-oestrogens linked to:
  • Endometriosis
  • Fibroids
  • Breast cancer
  • Dysmenorrhoea
  • Premenstrual syndrome (PMS)
  • Polycystic ovarian syndrome (PCOS) 
  • Endometriosis
  • Fibroids
  • PCO
  • Breast cancer
  • Reduced IVF success
  • Miscarriage
  • Premature delivery


Glucuronidation may be impaired in hypothyroidism40 and supporting glucuronidation may assist in oestrogendominant conditions where hypothyroidism is contributing. Clinically, this may be seen in patients presenting with conditions such as endometriosis, fibroids and fibrocystic breast disease.

CANCER

Numerous studies have identified increased levels of β-glucuronidase, either in the affected tissue or in the serum (Figure 5), in people with tumours.41,42 Table 2 lists the types of cancers found to be associated with elevated β-glucuronidase. Numerous animal studies have shown that oral administration of calcium Dglucarate decreases initiation, promotion and progression of experimental tumours induced by a variety of carcinogens.43 The results of animal studies have led researchers to suggest that that calcium D-glucarate may reduce the risk of lung, breast, prostate, liver, skin, and colon cancer in humans. 44
Calcium D-Glucarate Figure 5 Serum levels of β-glucuronidase in breast cancer - HealthMasters

Figure 5. Serum levels of β-glucuronidase in breast cancer patients compared to controls. 49

Table 2. Tumour types associated with elevated β-glucuronidase. 45,46,47,48

  • brain
  • breast
  • colon
  • liver
  • lung
  • pancreatic
  • penile
  • prostate
  • skin
  • stomach
  • uterus

GALLSTONES

Several lines of evidence support the use of calcium D-glucarate for the management of gallstones (cholelithiasis). β-glucuronidase activity in the liver and bile duct is suspected to play a pathogenic role in the condition by deconjugating glucuronidated bilirubin.50,51 One study found that people with cholesterol gallstones (the more common form) or pigment gallstones had 11- and 33-fold greater level of biliary β-glucuronidase than healthy controls, respectively. An animal study investigating the effect of 1,4 GL on bile function found that it significantly lowered biliary β-glucuronidase activity.52

DYSLIPIDAEMIA

Preliminary results investigating the lipid lowering effect of calcium D-glucarate found that it reduced total serum cholesterol up to 12 percent, LDL cholesterol up to 28 percent, and triglycerides up to 43 percent. The researchers suggests calcium D-glucarate lowered cholesterol by increasing excretion of bile acids. 53

CAUTIONS AND CONTRAINDICATIONS

CONTRAINDICATIONS

  • Digoxin: This drug is metabolised via glucuronidation and therefore levels may be affected by calcium-Dglucarate supplementation. Only use this combination under medical supervision.54,55,56,57

CAUTIONS

Diazepam/oxazepam: This drug is metabolised via glucuronidation and therefore levels may be affected by calcium-D-glucarate supplementation. Use with caution in patients taking this medication and monitor symptom changes. 58,59,60,61

Oral contraceptives: Calcium D-glucarate may reduce the efficacy of oral contraceptives. Calcium Dglucarate may impact on the metabolism and elimination of oestrogen via an action on beta-glucuronidase. Barrier forms of contraception may be required.62,63,64,65

PREGNANCY AND BREASTFEEDING

Pregnancy: Discontinue use if patient becomes pregnant whilst taking this formula. Oestrogen detoxification should be avoided during pregnancy.66,67

Breastfeeding: Likely safe when used at recommended doses.68,69

REFERENCES

1 Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9.
2 Oleson L, Court MH. Effect of the β-glucuronidase inhibitor saccharolactone on glucuronidation by human tissue microsomes and recombinant UDP-glucuronosyltransferases. J Pharm Pharmacol. 2008 Sep;60(9):1175-82.
3 Shimoi K, Nakayama T. Glucuronidase deconjugation in inflammation. Methods Enzymol. 2005;400:263-72.
4 Shapira I. et al. Evolving Concepts: How Diet and the Intestinal Microbiome Act as Modulators of Breast Malignancy. ISRN Oncol. 2013 Sep 25;2013:693920
5 Shimoi K, Nakayama T. Glucuronidase deconjugation in inflammation. Methods Enzymol. 2005;400:263-72.
6 Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2003 Jun;2(2):139-44.
7 Floriańczyk B, Grzybowska L . Activity of β-glucuronidase in blood serum of patients with breast cancer. J Chin Clin Med. 2010 August;5(8): 480-482.
8 Saluk-Juszczak J, Olas B, Nowak P, Staroń A, Wachowicz B. Protective effects of D-glucaro-1,4-lactone against oxidative modifications in blood platelets. Nutr Metab Cardiovasc Dis. 2008 Jul;18(6):422-8.
9 Zółtaszek R, Hanausek M, Kiliańska ZM, Walaszek Z. [The biological role of D-glucaric acid and its derivatives: potential use in medicine]. Postepy Hig Med Dosw (Online). 2008 Sep 5;62:451-62.
10 Zółtaszek R, Hanausek M, Kiliańska ZM, Walaszek Z. [The biological role of D-glucaric acid and its derivatives: potential use in medicine]. Postepy Hig Med Dosw (Online). 2008 Sep 5;62:451-62.
11 Saluk-Juszczak J, Olas B, Nowak P, Staroń A, Wachowicz B. Protective effects of D-glucaro-1,4-lactone against oxidative modifications in blood platelets. Nutr Metab Cardiovasc Dis. 2008 Jul;18(6):422-8.
12 Shimoi K, Nakayama T. Glucuronidase deconjugation in inflammation. Methods Enzymol. 2005;400:263-72.
13 Walaszek Z, Hanausek-Walaszek M. D-glucaro-1,4-lactone: its excretion In the bile and urine and effect on biliary excretion of β-glucuronidase after oral administration in rats. Hepatology 1988;9:552e7.
14 Oleson L, Court MH. Effect of the β-glucuronidase inhibitor saccharolactone on glucuronidation by human tissue microsomes and recombinant UDP-glucuronosyltransferases. J Pharm Pharmacol. 2008 Sep;60(9):1175-82.
15 Dwivedi C, Heck WJ, Downie AA, Larroya S, Webb TE. Effect of calcium glucarate on β-glucuronidase activity and glucarate content of certain vegetables and fruits. Biochem Med Metab Biol. 1990 Apr;43(2):83-92.
16 Dwivedi C, Heck WJ, Downie AA, Larroya S, Webb TE. Effect of calcium glucarate on β-glucuronidase activity and glucarate content of certain vegetables and fruits. Biochem Med Metab Biol. 1990 Apr;43(2):83-92.
17 Basińska A, Floriańczyk B. Β-glucuronidase in physiology and disease. Ann Univ Mariae Curie Sklodowska Med. 2003;58(2):386-9.
18 Zółtaszek R, Hanausek M, Kiliańska ZM, Walaszek Z. [The biological role of D-glucaric acid and its derivatives: potential use in medicine]. Postepy Hig Med Dosw (Online). 2008 Sep 5;62:451-62.
19 Dwivedi C, Heck WJ, Downie AA, Larroya S, Webb TE. Effect of calcium glucarate on β-glucuronidase activity and glucarate content of certain vegetables and fruits. Biochem Med Metab Biol. 1990 Apr;43(2):83-92.
20 Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2003 Jun;2(2):139-44.
21 Walaszek Z, Hanausek-Walaszek M, Minton JP, Webb TE. Dietary glucarate as anti-promoter of 7,12-dimethylbenz[a]anthraceneinduced mammary tumorigenesis. Carcinogenesis. 1986 Sep;7(9):1463-6.
22 Walaszek Z, Hanausek-Walaszek M, Minton JP, Webb TE. Dietary glucarate as anti-promoter of 7,12-dimethylbenz[a]anthraceneinduced mammary tumorigenesis. Carcinogenesis. 1986 Sep;7(9):1463-6.
23 Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9.
24 Shimoi K, Nakayama T. Glucuronidase deconjugation in inflammation. Methods Enzymol. 2005;400:263-72.
25 Zółtaszek R, Hanausek M, Kiliańska ZM, Walaszek Z. [The biological role of D-glucaric acid and its derivatives: potential use in medicine]. Postepy Hig Med Dosw (Online). 2008 Sep 5;62:451-62.
26 Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9.
27 Walaszek Z, Hanausek-Walaszek M, Minton JP, Webb TE. Dietary glucarate as anti-promoter of 7,12-dimethylbenz[a]anthraceneinduced mammary tumorigenesis. Carcinogenesis. 1986 Sep;7(9):1463-6.
28 Whiting JF, Narciso JP, Chapman V, Ransil BJ, Swank RT, Gollan JL. Deconjugation of bilirubin-IX alpha glucuronides: a physiologic role of hepatic microsomal β glucuronidase. J Biol Chem. 1993 Nov 5;268(31):23197-201.
29 Macfadyen A, Ho KJ. D-glucaro-1,4-lactone: its excretion in the bile and urine and effect on the biliary secretion of β-glucuronidase after oral administration in rats. Hepatology. 1989 Apr;9(4):552-6.
30 Bhattacharya S, Manna P, Gachhui R, Sil PC. D-saccharic acid 1,4-lactone protects diabetic rat kidney by ameliorating hyperglycemiamediated oxidative stress and renal inflammatory cytokines via NF-κB and PKC signaling. Toxicol Appl Pharmacol. 2013 Feb 15;267(1):16-29.
31 Saluk-Juszczak J, Olas B, Nowak P, Staroń A, Wachowicz B. Protective effects of D-glucaro-1,4-lactone against oxidative modifications in blood platelets. Nutr Metab Cardiovasc Dis. 2008 Jul;18(6):422-8.
32 Rashid K, Bhattacharya S, Sil PC. Protective role of D-saccharic acid-1,4-lactone in alloxan induced oxidative stress in the spleen tissue of diabetic rats is mediated by suppressing mitochondria dependent apoptotic pathway. Free Radic Res. 2012 Mar;46(3):240-52.
33 Cavalieri EL, Rogan EG. Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer. J Steroid Biochem Mol Biol. 2011 Jul;125(3-5):169-80.
34 Sasano H, Nagasaki S, Miki Y, Suzuki T. New developments in intracrinology of human breast cancer: estrogen sulfatase and sulfotransferase. Ann N Y Acad Sci. 2009 Feb;1155:76-9.
35 Ezaki K, Motoyama H, Sasaki H. Immunohistologic localization of estrone sulfatase in uterine endometrium and adenomyosis. Obstet Gynecol. 2001 Nov;98(5 Pt 1):815-9.
36 Wang M, Seippel L, Purdy RH, Bãckström T. Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20- one. J Clin Endocrinol Metab. 1996 Mar;81(3):1076-82.
37 Wang M, Seippel L, Purdy RH, Bãckström T. Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20- one. J Clin Endocrinol Metab. 1996 Mar;81(3):1076-82.
38 Stener-Victorin E, Holm G, Labrie F, Nilsson L, Janson PO, Ohlsson C. Are there any sensitive and specific sex steroid markers for polycystic ovary syndrome? J Clin Endocrinol Metab. 2010 Feb;95(2):810-9.
39 Rochester JR. Bisphenol A and human health: a review of the literature. Reprod Toxicol. 2013 Dec;42:132-55.
40 van der Heide SM, Joosten BJ, Everts ME, Klaren PH. Activities of UDP-glucuronyltransferase, β-glucuronidase and deiodinase types I and II in hyper- and hypothyroid rats. J Endocrinol. 2004 Jun;181(3):393-400.
41 Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2003 Jun;2(2):139-44.
42 Floriańczyk B, Grzybowska L . Activity of β-glucuronidase in blood serum of patients with breast cancer. J Chin Clin Med. 2010 August;5(8): 480-482.
43 Walaszek Z. Potential use of D-glucaric acid derivatives in cancer prevention. Cancer Lett. 1990;54:1-8.
44 Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2003 Jun;2(2):139-44.
45 Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9.
46 Saluk-Juszczak J, Olas B, Nowak P, Staroń A, Wachowicz B. Protective effects of D-glucaro-1,4-lactone against oxidative modifications in blood platelets. Nutr Metab Cardiovasc Dis. 2008 Jul;18(6):422-8.
47 Zółtaszek R, Hanausek M, Kiliańska ZM, Walaszek Z. [The biological role of D-glucaric acid and its derivatives: potential use in medicine]. Postepy Hig Med Dosw (Online). 2008 Sep 5;62:451-62.
48 Floriańczyk B, Grzybowska L . Activity of β-glucuronidase in blood serum of patients with breast cancer. J Chin Clin Med. 2010 August;5(8): 480-482.
49 Floriańczyk B, Grzybowska L . Activity of β-glucuronidase in blood serum of patients with breast cancer. J Chin Clin Med. 2010 August;5(8): 480-482.
50 Ho KJ, Hsu SC, Chen JS, Ho LH. Human biliary β-glucuronidase: correlation of its activity with deconjugation of bilirubin in the bile. Eur J Clin Invest. 1986 Oct;16(5):361-7.
51 Duvaldestin P, Mahu JL, Metreau JM, Arondel J, Preaux AM, Berthelot P. Possible role of a defect in hepatic bilirubin glucuronidation in the initiation of cholesterol gallstones. Gut. 1980 Aug;21(8):650-5.
52 Macfadyen A, Ho KJ. D-glucaro-1,4-lactone: its excretion in the bile and urine and effect on the biliary secretion of β-glucuronidase after oral administration in rats. Hepatology. 1989 Apr;9(4):552-6.
53 Walaszek Z, Hanausek-Walaszek M, Adams AK, Sherman U.Cholesterol lowering effects of dietary D-glucarate. FASEB 1991;5:A930; cited in Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9.
54 Calcium D-Glucarate Monograph. Alt Med Rev; 7(4)336-9.
55 Jellin JM, Ed. Natural Medicines Comprehensive Database. Calcium D-Glucarate. Therapeutic Research Faculty 2011; [webpage] http://www.naturaldatabase.com/ (date accessed: 9 January, 2014).
56 eMIMS. Amizide PI. UBM Medica Australia Pty Ltd. 2014.
57 Pharmacology Weekly. CytP450 Substrates. http://www.pharmacologyweekly.com/content/pages/cytochrome-cyp-p450-enzymemedication- herbs-substrates (date accessed 11 July 2014).
58 Calcium D-Glucarate Monograph. Alt Med Rev; 7(4)336-9.
59 Jellin JM, Ed. Natural Medicines Comprehensive Database. Calcium D-Glucarate. Therapeutic Research Faculty 2011; [webpage] http://www.naturaldatabase.com/ (date accessed: 9 January, 2014).
60 eMIMS. Amizide PI. UBM Medica Australia Pty Ltd. 2014.
61 Pharmacology Weekly. CytP450 Substrates. http://www.pharmacologyweekly.com/content/pages/cytochrome-cyp-p450-enzymemedication- herbs-substrates (date accessed 11 July 2014).
62 Calcium D-Glucarate Monograph. Alt Med Rev; 7(4)336-9.
63 Jellin JM, Ed. Natural Medicines Comprehensive Database. Calcium D-Glucarate. Therapeutic Research Faculty 2011; [webpage] http://www.naturaldatabase.com/ (date accessed: 9 January, 2014).
64 eMIMS. Amizide PI. UBM Medica Australia Pty Ltd. 2014.
65 Pharmacology Weekly. CytP450 Substrates. http://www.pharmacologyweekly.com/content/pages/cytochrome-cyp-p450-enzymemedication- herbs-substrates (date accessed 11 July 2014).
66 Calcium D-Glucarate Monograph. Alt Med Rev; 7(4)336-9.
67 Jellin JM, Ed. Natural Medicines Comprehensive Database. Calcium D-Glucarate. Therapeutic Research Faculty 2011; [webpage] http://www.naturaldatabase.com/ (date accessed: 9 January, 2014).
68 Calcium D-Glucarate Monograph. Alt Med Rev; 7(4)336-9.
69 Jellin JM, Ed. Natural Medicines Comprehensive Database. Calcium D-Glucarate. Therapeutic Research Faculty 2011; [webpage] http://www.naturaldatabase.com/ (date accessed: 9 January, 2014).