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.[1][2] Toxicity: guinea pig LD50 subcutaneous 18 mg/kg; mouse LD50 intraperitoneal 140 mg/kg and 300 mg/kg oral.[3] The log octanol-water partition coefficient (log P) 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.[4]
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.[5] Biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.[6]
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.[7] 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.[8] 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.[9][10][11]
The daily dose of buformin is 150–300 mg by mouth.[12] Buformin has also been available in a sustained release preparation, Silubin Retard, which is still sold in Romania.
The side effects encountered are anorexia, nausea, diarrhea, metallic taste, and weight loss. Its use is contraindicated in
diabetic coma, ketoacidosis, severe infection, trauma, other conditions 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.
Two 50mg buformin (Dibetos) tablets in blister pack from Nichi-Iko Pharmaceutical (Japan).
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,[13][14][15][16] Taiwan[17] and Japan (sold by Nichi-Iko Pharmaceutical Co., Ltd as "DIBETOS" tablets, each containing 50 mg buformin hydrochloride).[18] 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.[19][20][21]
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.[22]
Buformin, along with phenformin and metformin, inhibits the growth and development of cancer.[23][24][25][26][27] 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.[28] Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway.[29] Buformin decreased cancer incidence, multiplicity, and burden in chemically induced rat mammary cancer, whereas metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group.[30] Buformin also exhibits anti-proliferative and anti-invasive effects in endometrial cancer cells,[31] lung cancer cells[32] and cervical cancer cells.[33]
^Jacker HJ (1964). "[New Pharmacologic Products. 2. Buformin For Oral Therapy Of Diabetes]". Pharmazeutische Praxis. 10: 247–249. PMID14328846.
^Clarke EG, Berle J (1974). Isolation and identification of drugs in pharmaceuticals, body fluids and post-mortem material. Vol. 1. Pharmaceutical Press, Pharmaceutical Society of Great Britain. Dept. of Pharmaceutical Sciences. p. 226.
^Shroff JR, Bandurco V, Desai R, Kobrin S, Cervoni P (December 1981). "Chemistry and hypoglycemic activity of benzimidoylpyrazoles". Journal of Medicinal Chemistry. 24 (12): 1521–1525. doi:10.1021/jm00144a031. PMID7310831.
^United States National Library of Medicine ChemLDplus advanced database
^Ravina E, Kubinyi H (2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. Wiley. p. 215.
^Beckmann R, Lintz W, Schmidt-Böthelt E (September 1971). "Evaluation of a sustained release form of the oral antidiabetic butylbiguanide (Silubin retard)". European Journal of Clinical Pharmacology. 3 (4): 221–228. doi:10.1007/bf00565010. PMID5151304. S2CID39654704.
^Gutsche H, Blumenbach L, Losert W, Wiemann H (1976). "[Concentration of 14C-1-butylbiguanide in plasma of diabetic patients and its elimination after administration of a new Galenical formulation (author's transl)]". Arzneimittel-Forschung. 26 (6): 1227–1229. PMID989423.
^Ritzl F, Feinendegen LE, Lintz W, Tisljar U (1978). "[Distribution and excretion of 14c-butylbiguanide in man (author's transl)]". Arzneimittel-Forschung. 28 (7): 1184–1186. PMID582707.
^Kuschinsky G, Lüllmann H (1973). Textbook of pharmacology. Academic Press. p. 225.
^Hankó BZ, Reszegi CA, Kumli P, Vincze Z (2005). "[Practice of antidiabetic therapy in Hungary]". Acta Pharmaceutica Hungarica (in Hungarian). 75 (2): 77–86. PMID16318232.
^Schlesser JL (1990). Drugs available abroad. Gale Research Inc.; Derwent Publications, Ltd. p. 28.
^Chou CH, Cheng CL, Huang CC (May 2004). "A validated HPLC method with ultraviolet detection for the determination of buformin in plasma". Biomedical Chromatography. 18 (4): 254–258. doi:10.1002/bmc.312. PMID15162388.
^Wurita A, Hasegawa K, Nozawa H, Yamagishi I, Minakata K, Watanabe K, Suzuki O (September 2020). "Postmortem distribution/redistribution of buformin in body fluids and solid tissues in an autopsy case using liquid chromatography-tandem mass spectrometry with QuEChERS extraction method". Forensic Science International. 314: 110376. doi:10.1016/j.forsciint.2020.110376. PMID32615395. S2CID220328342.
^Wittmann P, Haslbeck M, Bachmann W, Mehnert H (January 1977). "[Lactic acidosis in diabetics on biguanides (author's transl)]". Deutsche Medizinische Wochenschrift (in German). 102 (1): 5–10. doi:10.1055/s-0028-1104832. PMID11984. S2CID260117450.
^Berger W, Mehnert-Aner S, Mülly K, Heierli C, Ritz R (December 1976). "[10 cases of lactic acidosis during biguanide therapy (buformin and phenformin)]". Schweizerische Medizinische Wochenschrift. 106 (50): 1830–1834. PMID1013709.
^Deppermann D, Heidland A, Ritz E, Hörl W (September 1978). "[Lactic acidosis--a possible complication in buformin-treated diabetics (author's transl)]". Klinische Wochenschrift. 56 (17): 843–853. doi:10.1007/BF01479834. PMID713413. S2CID39728557.
^Anisimov VN (October 2003). "Insulin/IGF-1 signaling pathway driving aging and cancer as a target for pharmacological intervention". Experimental Gerontology. 38 (10): 1041–1049. doi:10.1016/s0531-5565(03)00169-4. PMID14580857. S2CID27811309.
^Alexandrov VA, Anisimov VN, Belous NM, Vasilyeva IA, Mazon VB (1980). "The inhibition of the transplacental blastomogenic effect of nitrosomethylurea by postnatal administration of buformin to rats". Carcinogenesis. 1 (12): 975–978. doi:10.1093/carcin/1.12.975. PMID11272113.
^Anisimov VN, Ostroumova MN, Dil'man VM (June 1980). "[Inhibition of the blastomogenic effect of 7,12-dimethylbenz(a)anthracene in female rats by buformin, diphenin, a polypeptide pineal extract and L-DOPA]". Biulleten' Eksperimental'noi Biologii I Meditsiny. 89 (6): 723–725. doi:10.1007/bf00836263. PMID6772259. S2CID46058518.
^Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Tyndyk ML, et al. (December 2005). "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 (1): 220–234. Bibcode:2005NYASA1057..220A. doi:10.1196/annals.1356.017. PMID16399897. S2CID5744858.
^Fara GM, Lugaro G, Galli MG, Giannattasio G (April 1974). "Antiviral activity of selected biguanide derivatives". Pharmacological Research Communications. 6 (2): 117–126. doi:10.1016/s0031-6989(74)80019-6. PMID4373765.
^Denys A, Bocian J (March 1970). "[Effect of Silubin-retard (1-butyl-biguanide hydrochloride) on the course of influenza-virus infection in mice]". Polski Tygodnik Lekarski (in Polish). 25 (9): 332–334. PMID5447272.
^Babiński S, Giermaziak H (November 1973). "[Influenza epidemic in 1971 in diabetics treated with 1-butyl-biguanidine hydrochloride (Silubin retard) and 1-phenylethyl-biguanidine hydrochloride (Phenformin)]". Polski Tygodnik Lekarski (in Polish). 28 (46): 1815–1817. PMID4771858.
^US 2961377, Shapiro SL, Freedman L, "Salts Of N-Amylbiguanide.", issued 1960, assigned to US Vitamin and Pharmaceutical Corp
^Shapiro SL, Parrino VA, Freedman L (1959). "Hypoglycemic Agents. III.1—3N1-Alkyl- and Aralkylbiguanides". Journal of the American Chemical Society. 81 (14): 3728–3736. doi:10.1021/ja01523a060.
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