Buformin

Buformin
Names
Other names
N-Butylimidocarbonimidic diamide
Identifiers
ATC code A10BA03
692-13-7 Yes
ChEMBL ChEMBL39736 Yes
ChemSpider 2374 Yes
DrugBank DB04830
EC number 211-726-4
Jmol-3D images Image
Image
KEGG D00595 Yes
MeSH Buformin
PubChem 2468
UNII W2115E9C7B Yes
Properties
Molecular formula
 C6H15N5
Molar mass 157.22 g·mol−1
log P -1.2[1]
Pharmacology
Oral
Excretion Renal
Related compounds
Related compounds
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

Buformin (1-butylbiguanide) is an oral antidiabetic drug of the biguanide class, chemically related to metformin and phenformin. Buformin was marketed by German pharmaceutical company Grünenthal as Silubin.

Chemistry and animal toxicology

Buformin hydrochloride is a fine, white to slightly yellow, crystalline, odorless powder, with a weakly acidic bitter taste. Its melting point is 174 to 177 °C, it is a strong base, and is freely soluble in water, methanol and ethanol, but insoluble in chloroform and ether.[2][3] Toxicity: guinea pig LD50 subcutaneous 18 mg/kg; mouse LD50 intraperitoneal 140 mg/kg and 300 mg/kg oral.[4] The partition coefficient (log P in octanol-water) is -1.20E+00; its water solubility is 7.46E+05 mg/l at 25 °C. Vapor pressure is 1.64E-04 mm Hg at 25 °C (EST); Henry's law constant is 8.14E-16 atm-m3/mole at 25 °C (EST). Its Atmospheric -OH rate constant is 1.60E-10 cm3/molecule-sec at 25 °C.[5]

Mechanism of action

Buformin delays absorption of glucose from the gastrointestinal tract, increases insulin sensitivity and glucose uptake into cells, and inhibits synthesis of glucose by the liver. Buformin and the other biguanides are not hypoglycemic, but rather antihyperglycemic agents. They do not produce hypoglycemia; instead, they reduce basal and postprandial hyperglycemia in diabetics.[6] Biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.[7]

Pharmacokinetics

After oral administration of 50 mg of buformin to volunteers, almost 90% of the applied quantity was recovered in the urine; the rate constant of elimination was found to be 0.38 per hr. Buformin is a strong base (pKa = 11.3) and not absorbed in the stomach. After intravenous injection of about 1 mg/kg buformin-14-C, the initial serum concentration is 0.2-0.4 µg/ml. Serum level and urinary elimination rate are linearly correlated.[8] In man, after oral administration of 50 mg 14-C-buformin, the maximum serum concentration was 0.26-0.41 µg/ml. The buformin was eliminated with an average half-life of 2 h. About 84% of the dose administered was found excreted unchanged in the urine.[9] Buformin is not metabolized in humans. The bioavailability of oral buformin and other biguanides is 40%-60%. Binding to plasma proteins is absent or very low.[10][11][12]

Dosage

The daily dose of buformin is 150–300 mg by mouth.[13] Buformin has also been available in a sustained release preparation, Silubin Retard, which is still sold in Romania.

Side effects and cotraindications

The side effects encountered are anorexia, nausea, diarrhea, metallic taste, and weight loss. Its use is contrindicated by diabetic coma, ketoacidosis, severe infection, trauma, other severe infections where buformin is unlikely to control the hyperglycemia, renal or hepatic impairment, heart failure, recent myocardial infarct, dehydration, alcoholism, and conditions likely to predispose to lactic acidosis.

Toxicity

Buformin was withdrawn from the market in many countries due to an elevated risk of causing lactic acidosis (although not the US, where it was never sold). Buformin is still available and prescribed in Romania (timed release Silubin Retard is sold by Zentiva), Hungary,[14][15][16][17] Taiwan[18] and Japan.[19] The lactic acidosis occurred only in patients with a buformin plasma level of greater than 0.60 µg/ml and was rare in patients with normal renal function.[20][21][22] In one report, the toxic oral dose was 329 ± 30 mg/day in 24 patients who developed lactic acidosis on buformin. Another group of 24 patients on 258 ± 25 mg/day did not develop lactic acidosis on buformin.[23]

Anticancer properties

Buformin, along with phenformin and metformin, inhibits the growth and development of cancer.[24][25][26][27][28] The anticancer property of these drugs is due to their ability to disrupt the Warburg effect and revert the cytosolic glycolysis characteristic of cancer cells to normal oxidation of pyruvate by the mitochondria.[29] Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway.[30]

History

Buformin was synthesized as an oral antidiabetic in 1957.[31]

References

  1. ↑ F. Macdonald. Dictionary of pharmacological agents: Volumes 1-2 - Page 344, 1997
  2. ↑ Jacker HJ. [New Pharmacologic Products. 2. Buformin For Oral Therapy Of Diabetes]. Pharm Prax. 1964;10:247-9.
  3. ↑ Eustace George Coverly Clarke, Judith Berle, Pharmaceutical Society of Great Britain. Dept. of Pharmaceutical Sciences. Isolation and identification of drugs in pharmaceuticals, body fluids and post-mortem material, Volume 1. Pharmaceutical Press 1974, p226
  4. ↑ Shroff JR, Bandurco V, Desai R, Kobrin S, Cervoni P. Chemistry and hypoglycemic activity of benzimidoylpyrazoles. J Med Chem 1981 Dec;24(12):1521-5.
  5. ↑ United States National Library of Medicine ChemLDplus advanced database
  6. ↑ Enrique Ravina, Hugo Kubinyi. The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. Wiley. 2011 p 215
  7. ↑ Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013 Feb 14;494(7436):256-60. doi: 10.1038/nature11808. Epub 2013 Jan 6. PMID 23292513
  8. ↑ Beckmann R. The fate of biguanides in man. Ann N Y Acad Sci. 1968 Mar 26;148(3):820-32.
  9. ↑ Beckmann R, Lintz W, Schmidt-Böthelt E. Evaluation of a sustained release form of the oral antidiabetic butylbiguanide (Silubin retard). Eur J Clin Pharmacol. 1971 Sep;3(4):221-8.
  10. ↑ Marchetti P, Giannarelli R, di Carlo A, Navalesi R. Pharmacokinetic optimisation of oral hypoglycaemic therapy. Clin Pharmacokinet. 1991 Oct;21(4):308-17 PMID 1760902
  11. ↑ Gutsche H, Blumenbach L, Losert W, Wiemann H. Concentration of 14C-1-butylbiguanide in plasma of diabetic patients and its elimination after administration of a new Galenical formulation. Arzneimittelforschung 1976;26(6):1227-9
  12. ↑ Ritzl F, Feinendegen LE, Lintz W, Tisljar U. Distribution and excretion of 14c-butylbiguanide in man. Arzneimittelforschung 1978;28(7):1184-6
  13. ↑ Gustav Kuschinsky, Heinz Lüllmann. Textbook of pharmacology. Academic Press p 225, 1973
  14. ↑ Hankó B, Tukarcs E, Kumli P, Vincze Z. Antidiabetic drug utilization in Hungary. Pharm World Sci. 2005 Jun;27(3):263-5.
  15. ↑ Hankó BZ, Reszegi CA, Kumli P, Vincze Z. [Practice of antidiabetic therapy in Hungary]. Acta Pharm Hung. 2005;75(2):77-86.
  16. ↑ Jerry L. Schlesser, Gale Research Inc. Drugs available abroad. Derwent Publications, Ltd - 1990 p28
  17. ↑ Verdonck L, Sangster B, van Heijst A, de Groot G, Maes R (1981). "Buformin concentrations in a case of fatal lactic acidosis". Diabetologia 20 (1): 45–6. doi:10.1007/BF01789112. PMID 7202882.
  18. ↑ Chou CH, Cheng CL, Huang CC. A validated HPLC method with ultraviolet detection for the determination of buformin in plasma. Biomed Chromatogr. 2004 May;18(4):254-8.
  19. ↑ Takeda Announces Submission Of Application For Additional Indication Of Actos In Japan; Concomitant Therapy With Biguanides For Type 2 Diabetes. Medical News Today. 28 Jan 2007
  20. ↑ Wittmann P, Haslbeck M, Bachmann W, Mehnert H. [Lactic acidosis in diabetics on biguanides (author's translation)] Deutsche Medizinische Wochenschrift 102(1):5-10, 1977
  21. ↑ Berger W, Mehnert-Aner S, Mülly K, Heierli C, Ritz R. [10 cases of lactic acidosis during biguanide therapy (buformin and phenformin)]. Schweizerische medizinische Wochenschrift. 106:1830-1834, 1976
  22. ↑ Deppermann D, Heidland A, Ritz E, Hörl W (1978). "[Lactic acidosis--a possible complication in buformin-treated diabetics (author's transl)]". Klin Wochenschr 56 (17): 843–53. PMID 713413.
  23. ↑ Luft D, Schmülling RM, Eggstein M. Lactic acidosis in biguanide-treated diabetics: a review of 330 cases. Diabetologia. 1978 Feb;14(2):75-87.
  24. ↑ Sakae Saito, Aki Furuno, Junko Sakurai, Asami Sakamoto, Hae-Ryong Park, Kazuo Shin-ya, Takashi Tsuruo, and Akihiro Tomida. Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation. Cancer Research 2009;69(10):4225–34
  25. ↑ Vladimir N. Anisimov. Insulin/IGF-1 signaling pathway driving aging and cancer as a target for pharmacological intervention. Experimental Gerontology Volume 38, Issue 10, October 2003, Pages 1041-1049
  26. ↑ Valery A. Alexandrov, Vladimir N. Anisimov, Natalia M. Belous, Inna A. Vasilyeva and Vera B. Mazon. The inhibition of the transplacental blastomogenic effect of nitrosomethylurea by postnatal administration of buformin to rats. Carcinogenesis Volume 1, Issue 12 Pp. 975-978, 1980
  27. ↑ Anisimov VN, Ostroumova MN, Dil'man VM. Inhibition of the blastomogenic effect of 7,12-dimethylbenz(a)anthracene in female rats by buformin, diphenin, a polypeptide pineal extract and L-DOPA. Bulletin of Experimental Biology and Medicine. Volume 89, Number 6, 819-822, 1980
  28. ↑ Vladimir N. Anisimov, Lev M. Berstein, Irina G. Popovich, Mark A. Zabezhinski, Peter A. Egormin, Margarita L. Tyndyk, Ivan V. Anikin, Anna V. Semenchenko, Anatoli I. Yashin. Central and Peripheral Effects of Insulin/IGF-1 Signaling in Aging and Cancer: Antidiabetic Drugs as Geroprotectors and Anticarcinogens. Annals of the New York Academy of Sciences. 1057:220-234, 2005
  29. ↑ Matthew G. Vander Heiden, Lewis C. Cantley, and Craig B. Thompson. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 324 (5930): 1029-1033, 2009.
  30. ↑ Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005 Dec 9;310(5754):1642-6.
  31. ↑ Seymour L. Shapiro et al. Salts Of N-Amylbiguanide. US Patent number: 2961377; Filing date: Aug 5, 1957; Issue date: 1960