# Metformin

##### Metformin, first-line therapy of type 2 Diabetes Mellitus

Enrico Canuto, Former Faculty, Politecnico di Torino

Torino, July 10,2020

Draft

###### Introduction

Metformin is a trade name of dimethyl-biguanide (see Figure 1), a first-line therapy in the treatment of type 2 diabetes mellitus (T2DM), which is well tolerated by the majority of patients [2]. Metformin lowers both basal and postprandial plasma glucose. It works by inhibiting the production of hepatic glucose, by reducing intestinal glucose absorption and by improving glucose utilization. But the glycemic response  to metformin is rather variable from patient to patient.

To make the medicament water-soluble, the salt dimethyl-biguanide hydrocloride is produced.

Figure 1 - Chemical structure of metformin. The red ellipse marks the different structure from galegine (see Figure 2)

The biguanide class of antidiabetic medications originates from the blooming of Gàlega Officinalis (also known as French lilac, Goat’s rue, Italian fitch, Gàlega o Capraggine in Italian, probably from Medieval Latin (herba) gallica, coherent with French lilac, Figure 2, left). At least since medieval times, Galega was said to relieve the intense urination accompanying the disease that came to have the name of diabetes mellitus [1].  The active ingredient in the French lilac that lowers blood glucose was shown to be galegine (Figure 2, right). Though used as antidiabetic medicament in the early XX century, it was soon supplanted by alternatives because of its toxicity. The current alternative is metformin, already discovered in the early XX century but recognized as an effective antidiabetic medicament only after the II World War by the French diabetologist J. Sterne, who, studying antidiabetic properties of galegine, noticed the related chemical structures and found earlier positive reports of antidiabetic efficacy.



Figure 2 - Left: Gàlega officinalis, from Wikipedia.
Right: Galegine chemical structure. The red ellipse marks the different structure from metformin (Figure 1). 
###### Chemical structure

To understand the chemical formula of metformin (Figure 1) we start from ammonia (NH3), a  common compound of nitrogen (N, the most abundant element of the Earth’s atmosphere) and hydrogen (H). Ammonia molecule has four outer electron pairs that are arranged in a tetrahedron: three pairs are bond pairs with three hydrogen ions, the fourth one is a lone pair (a pair of valence electrons that are not shared with other atoms). Hydrogen atoms can be replaced by myriad substituents.

1) We are interested in the amino functional group (-NH2), where one hydrogen atom is replaced by other groups of atoms (radicals), denoted by R. The resulting class of molecules RNH2 is known as primary amine. Amino acids, the bricks of the proteins, belong to this class.  The secondary amine is a class of molecules with a single hydrogen atom R1R2NH and two radicals.

Figure 3 - Chemical structure of dimethyl-amine.

2) A second functional group of interest is methyl group, –CH3, where a carbon atom is bonded to three hydrogen atoms and to a radical. The group occurs in many organic compounds as a very stable group. The name is back formation from methylene, introduced around 1840 by French chemists J-B. Dumas and E. Peligot from ancient Greek $\mu&space;\grave{\epsilon&space;}\theta&space;\upsilon$, wine, and $\grave{\upsilon&space;}\lambda&space;\eta$, wood, substance, to indicate methanol, of which they found the elemental composition. Metformin synthesis involves dimethyl-amine (Figure 3) a secondary amine group bonded to a pair of methyl groups.

Figure 4 - Chemical structure of nitrile.



3) A third functional group of interest is nitrile RCN (Figure 4, cyano- in the compounds, inorganic compounds are known as cyanides). The first cyanide, the prussic acid (hydrogen cyanide, HCN), was synthesized by the Swedish Pomeramian (German speaking) pharmaceutical chemist C.W. Scheele in 1782, who discovered several elements and compounds (including organic acids) later attributed to other chemists. C.W. Scheele gave it the name of ‘blue acid’ since derived from the Prussian blue pigment. The ancient Greek name for blue is κυανοῦς, the source of cyan and it derivatives.

Figure 5 - Top, chemical structure of guanidine. Bottom, chemical structure of 2-cyanoguanidine.

4) The next step is the guanidine HNC(NH2)2 , (Figure 5, top) isolated in 1861 by German chemist W. Strecker, known for his work on amino acids. A carbon atom bonds with a pair of amino groups -NH2 and with the secondary amine group –NH. Guanidine is a strong base used for producing plastics and explosives. The name is a formation from Spanish guano, dung of sea-birds, in turn from Quechua huanu, dung, since it was derived by degradation of the aromatic base guanine, in turn obtained from Peruvian guano. Metformin synthesis involves the 2-cyano-guanidine, (H2N)2C=NCN (Figure 5, bottom), a slow fertilizer. The hydrogen atom of the guanidine is replaced by the nitrile (cyano-) functional group.

5) The last component is the hydrochloride acid HCl which is made to react with organic bases, such a amines, to create hydrochlorides. They are water-soluble salts, suitable to medicaments. In this case, metformin hydrochloride is obtained from dimethyl-amine hydrochloride, written as $(CH_{3})_{2}NH\cdot&space;HCl$.

Essentially, the manufacturing process dissolves equimolar amounts of dimethyl-amine hydrochloride and 2-cyano-guanidine in a solvent. The mixture boils and after cooling precipitates yielding metformin hydrochloride (Figure 6).

Figure 6 - Chemical reaction producing metformin hydrochloride
###### Pharmacokinetics

Metformin is not metabolized and is excrete unchanged in the urine, with a time constant of about 5 h. The mean renal clearance is about $500\pm&space;100\,&space;\textup{ml/min}$ [2].  The steady state metformin plasma concentration is extremely variable from patient to patient $0.050\sim&space;4&space;\,&space;\mu&space;\textup{g/ml}$. Variability is expected to be related to the genes mediating the diverse pharmacological responses to metformin treatment [2]. The main pathway from oral administration to elimination through urine is sketched in Figure 7 (from [2]).

Figure 7 - Pathway of oral metformin (simplified from [2])

Besides other health benefits like weight reduction, metformin is known to cause gastrointestinal upset (in most cases diarrhea)  in about 30% of patients, especially when it is first administered, or when the dose is increased [3]. The mechanism of gastrointestinal intolerance is still unclear. Different hypotheses have been proposed, including stimulation of the serotonin intestinal secretion [4], alteration of glucose metabolism and malabsorption of bile salts.

TBC

###### References

[1] L.A. Witters, The blooming of the French Lilac, J. Clinical Invest., Vol. 108, 2001, pp. 1005-1007.

[2] L. Gong, S. Goswani, K.M. Giacomini, R.B. Altman and T.E. Klein, Metformin pathways: pharmacokinetics and pharmacodynamics, Pharmacogenet Genomics, Vol. 22 , No. 11, November 2012, pp. 820-827.

[3] M. Fatima, S. Sadeeqa nad S.U.R. Nazir, Metformin and its gastrointestinal problems: a review, Biomedical Research, Vol. 29, No.11, 2018, pp. 2285-2289.

[4] L.X. Cubeddu,H. Bönisch, M. Göthert, G. Molderings, K. Racké, G. Ramadori, K.J. Miller and H. Schwörer, Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors, Naunyn-Schmiedeberg’s Archives of Pharmacology, Vol.361, 2000, pp.85-91.