Monograph
A12AX - Calcium, Combinations with Vitamin D and/or Other Drugs |
Propably not porphyrinogenic |
PNP |
Important Information
Limitations: This safety classification applies only to preparations containing a combination of the two drugs calcium carbonate and vitamin D3. The same ATC code (A12AX) can in some countries be used for different combinations of calcium and other drugs, which in theory may or may not be porphyrinogenic. Please refer to the classification and monograph of each individual substance.
Rationale
Calcium carbonate has been used uneventfully by 26 carriers of acute porphyria. Vitamin D3 is metabolized by CYP3A4 and has been suspected to induce CYP3A4 via the vitamin D receptor in vitro. There are no relevant drug-drug interactions with calcium or vitamin D3 as perpetrator.
Chemical description
Calcium carbonate
Colecalciferol belongs to tripertenoids
Therapeutic characteristics
Calcium in combination with vitamin D3 is used in the treatment and prevention of calcium and vitamin D deficiency in elderly, and in the adjunctive treatment of osteoporosis.
Metabolism and pharmacokinetics
Calcium carbonate is eliminated through faeces, urine and sweat (SPC). Calcium carbonate is individually classified as not porphyrinogenic and has been used uneventfully by 26 acute porphyria patients (see monograph, ATC-code: A12AA04).
Colecalciferol is converted to its active form, 1α-25-dihydroxycolecalciferol, by two hydroxylations (SPC). It is metabolized in the kidney by CYP24 (24-hydroxylase) and CYP27B1 (alpha-hydroxylase) (Inouye 2001), and CYP3A4 in the liver and small intestine (Xu 2006).
In vitro studies have reported that vitamin D3 is an inducer of intestinal CYP3A4 (Thompson 2002 and Thummel 2001) and CYP3A4, 2B6 and 2C9 in human hepatocytes (Drocourt 2002). Vitamin D3 is suspected to induce CYP3A4 via binding to the vitamin D receptor (VDR) (Thummel 2001).
The VDR forms a heterodimer with RXR and this complex is thought to bind to the CYP3A4 ER6 promotor element (PXR response element), promoting transcription. Vitamin D3 was not found to activate PXR or CAR (Thummel 2001).
Neither calcium carbonate nor vitamin D3 is suspected to be an inducer or a mechanism-based inhibitor of CYP enzymes in vivo (Hisaka 2010, Isoherranen 2009, Pelkonen 2008). There are no relevant drug-drug interactions with calcium in combination with vitamin D3 as perpetrators reported in the literature (interaktionsdatabasen.dk, SPC).
References
| # |
Citation details |
PMID |
|---|
| * | Scientific articles |
| 1. |
Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes.
Drocourt L, Ourlin JC, et al. J Biol Chem. 2002 Jul 12;277(28):25125-32. |
11991950 |
| 2. |
Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information.
Hisaka A, Ohno Y, et al. Pharmacol Ther. 2010 Feb;125(2):230-48. |
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| 3. |
Enzymatic studies on the key enzymes of vitamin D metabolism; 1 alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24).
Inouye K, Sakaki T. Biotechnol Annu Rev. 2001;7:179-94. |
11686044 |
| 4. |
Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database.
Isoherranen N, Hachad H, et al. Chem Res Toxicol. 2009 Feb;22(2):294-8. |
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| 5. |
Inhibition and induction of human cytochrome P450 enzymes: current status.
Pelkonen O, Turpeinen M, et al. Arch Toxicol. 2008 Oct;82(10):667-715. |
18618097 |
| 6. |
Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements.
Thompson PD, Jurutka PW, et al. Biochem Biophys Res Commun. 2002 Dec 20;299(5):730-8. |
12470639 |
| 7. |
Transcriptional control of intestinal cytochrome P-4503A by 1alpha,25-dihydroxy vitamin D3.
Thummel KE, Brimer C, et al. Mol Pharmacol. 2001 Dec;60(6):1399-406. |
11723248 |
| 8. |
Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia.
Xu Y, Hashizume T, et al. Mol Pharmacol. 2006 Jan;69(1):56-65. |
16207822 |
| * | Drug interaction databases |
| 9. |
Interaktionsdatabasen. Calcichew-D3.
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| * | Summary of Product Characteristics |
| 10. |
The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). (Calcichew-D3).
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