Created page with "<!-- Adverse effects --> メトホルミンは一般的に忍容性が高い。一般的な副作用には、下痢、吐き気、腹痛などがある。メトホルミンは低血糖を引き起こすリスクが小さい。高血中乳酸値（アシドーシス）は、医薬品を過度に大量に使用したり、重度の腎障害のある人に処方..."
Metformin is a [[biguanide]] anti-[[Hyperglycemia|hyperglycemic]] agent. It works by decreasing [[Gluconeogenesis|glucose production]] in the [[liver]], increasing the insulin sensitivity of body tissues,
Metformin was first described in scientific literature in 1922 by Emil Werner and James Bell. French physician Jean Sterne began the study in humans in the 1950s. It was introduced as a medication in France in 1957 and the United States in 1995. Metformin is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]], and is the most widely used medication for diabetes taken by mouth. It is available as a [[generic medication]]. In 2021, it was the second most commonly prescribed medication in the United States, with more than 91{{nbsp}}million prescriptions.
メトホルミンは、1922年にEmil WernerとJames Bellによって初めて科学文献に記載された。フランスの医師ジャン・スターン（Jean Sterne）は1950年代にヒトでの研究を開始した。フランスでは1957年に、米国では1995年に医薬品として導入された。メトホルミンは[[WHO Model List of Essential Medicines/ja|世界保健機関の必須医薬品リスト]]に掲載されており、口から服用する糖尿病治療薬として最も広く使用されている。[[generic medication/ja|ジェネリック医薬品]]としても販売されている。2021年には、米国で2番目に多く処方された医薬品であり、91{{nbsp}}万以上の処方があった。
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== 医療用途 ==
== Medical uses ==
{{Anchor|Medical uses}}
Metformin is used to lower the blood glucose in those with type{{nbsp}}2 diabetes. It is also used as a second-line agent for [[infertility]] in those with polycystic ovary syndrome.
[[American Diabetes Association/ja|米国糖尿病学会]]と[[:en:American College of Physicians|米国内科学会]]はともに、メトホルミンを2型糖尿病治療の第一選択薬として推奨している。メトホルミンは[[repaglinide/ja|レパグリニド]]と同程度に有効であり、2型糖尿病に対する他のすべての経口薬物よりも有効である。
The [[American Diabetes Association]] and the [[American College of Physicians]] both recommend metformin as a first-line agent to treat type{{nbsp}}2 diabetes. It is as effective as [[repaglinide]] and more effective than all other oral drugs for type{{nbsp}}2 diabetes.
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==== 有効性 ====
==== Efficacy ====
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[[:en:European Association for the Study of Diabetes|欧州糖尿病学会]]、欧州心臓病学会、[[American Diabetes Association/ja|米国糖尿病学会]]などの主要な専門学会の治療ガイドラインでは、メトホルミンの心血管ベネフィットに関するエビデンスは曖昧であると記述されている。2020年の[[:en:Cochrane (organization)|コクラン]]では [[systematic review/ja|システマティックレビュー]]では、メトホルミン単剤療法を他の糖低下薬物、行動変容介入、プラセボ、介入なしと比較した場合、心血管死亡率、非致死的[[myocardial infarction/ja|心筋梗塞]]、非致死的[[stroke/ja|脳卒中]]の減少を示す十分なエビデンスは認められなかった。
Treatment guidelines for major professional associations, including the [[European Association for the Study of Diabetes]], the European Society for Cardiology, and the [[American Diabetes Association]], describe evidence for the cardiovascular benefits of metformin as equivocal. A 2020 [[Cochrane (organization)|Cochrane]] [[systematic review]] did not find enough evidence of reduction of cardiovascular mortality, non-fatal [[myocardial infarction]] or non-fatal [[stroke]] when comparing metformin monotherapy to other glucose-lowering drugs, behavior change interventions, placebo or no intervention.
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メトホルミンの使用は、体重増加と関連する[[sulfonylurea/ja|スルホニル尿素]]とは対照的に、2型糖尿病患者の体重を減少させる。メトホルミンが糖尿病がない肥満の体重減少に関連することを示す証拠もある。メトホルミンはスルホニル尿素系薬剤よりも[[hypoglycemia/ja|低血糖]]のリスクが低いが、低血糖は激しい運動、カロリー不足、または血糖を低下させる他の薬剤との併用時に起こることがまれである。メトホルミンは、[[low density lipoprotein/ja|低密度リポ蛋白]]および[[triglyceride/ja|トリグリセリド]]値を緩やかに低下させる。
The use of metformin reduces body weight in people with type{{nbsp}}2 diabetes in contrast to [[sulfonylurea]]s, which are associated with weight gain. Some evidence shows that metformin is associated with weight loss in obesity in the absence of diabetes. Metformin has a lower risk of [[hypoglycemia]] than the sulfonylureas, although hypoglycemia has uncommonly occurred during intense exercise, calorie deficit, or when used with other agents to lower blood glucose. Metformin modestly reduces [[low density lipoprotein]] and [[triglyceride]] levels.
In individuals with [[prediabetes]], a 2019 [[systematic review]] comparing the effects of metformin with other interventions in the reduction of risk of developing type{{nbsp}}2 diabetes found moderate-quality evidence that metformin reduced the risk of developing type{{nbsp}}2 diabetes when compared to diet and exercise or a [[placebo]]. However, when comparing metformin to intensive diet or exercise, moderate-quality evidence was found that metformin did not reduce risk of developing type{{nbsp}}2 diabetes and very low-quality evidence was found that adding metformin to intensive diet or exercise did not show any advantage or disadvantage in reducing risk of type{{nbsp}}2 diabetes when compared to intensive exercise and diet alone. The same review also found one suitable trial comparing the effects of metformin and [[sulfonylurea]] in reducing risk of developing type{{nbsp}}2 diabetes in prediabetic individuals, however this trial did not report any patient relevant outcomes.
In those with polycystic ovarian syndrome (PCOS), tentative evidence shows that metformin use increases the rate of live births. This includes in those who have not been able to get pregnant with clomiphene. Metformin does not appear to change the risk of miscarriage. A number of other benefits have also been found both during pregnancy and in nonpregnant women with PCOS. In an updated Cochrane (2020) review on metformin versus placebo/no treatment before or during [[In vitro fertilisation|IVF/ICSI]] in women with PCOS no conclusive evidence of improved live birth rates was found. In long [[Gonadotropin-releasing hormone agonist|GnRH-agonist]] protocols there was uncertainty in the evidence of improved live birth rates but there could be increases in clinical pregnancy rate. In short [[GNRH antagonist|GnRH-antagonist]] protocols metformin may reduce live birth rates with uncertainty on its effect on clinical pregnancy rate. Metformin may result in a reduction of [[Ovarian hyperstimulation syndrome|OHSS]] but could come with a greater frequency of side effects. There was uncertainty as to metformin's impact on miscarriage. The evidence does not support general use during pregnancy for improving maternal and infant outcomes in obese women.
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イギリスの[[:en:National Institute for Health and Clinical Excellence|米国国立医療技術評価機構]]は2004年に、PCOSで[[body mass index/ja|肥満度]]が25を超える女性に対して、他の治療法で効果が得られない場合に[[anovulation/ja|無排卵]]と[[infertility/ja|不妊]]のためにメトホルミンを投与することを推奨した。英国および国際的な[[clinical practice guideline/ja|臨床実践ガイドライン]]では、[[glucose intolerance/ja|耐糖能異常]]のある女性を除き、メトホルミンを第一選択治療として推奨していないか、まったく推奨していない。ガイドラインでは、クロミフェンを第一選択医薬品として推奨し、内科的治療とは別に生活習慣の改善を強調している。メトホルミン治療は、ベースライン時に耐糖能障害を示したPCOS女性における2型糖尿病の発症リスクを低下させる。
The United Kingdom's [[National Institute for Health and Clinical Excellence]] recommended in 2004 that women with PCOS and a [[body mass index]] above 25 be given metformin for [[anovulation]] and [[infertility]] when other therapies fail to produce results. UK and international [[clinical practice guideline]]s do not recommend metformin as a first-line treatment or do not recommend it at all, except for women with [[glucose intolerance]]. The guidelines suggest clomiphene as the first medication option and emphasize lifestyle modification independently from medical treatment. Metformin treatment decreases the risk of developing type{{nbsp}}2 diabetes in women with PCOS who exhibited impaired glucose tolerance at baseline.
Gastric cancer (GC) stands as a major global health concern due to its high prevalence and mortality rate. Amidst various treatment avenues, metformin, a common medication for type-2 [[diabetes mellitus]] (T2DM), has garnered attention for its potential anti-cancer properties. While its effectiveness in combating GC has been a subject of debate, recent clinical studies predominantly support metformin's protective impact on reducing the risk and improving the survival rates of GC patients. The drug's anti-cancer effects are believed to be mediated through multiple pathways, particularly involving AMPK activation and IGF-1R modulation. Despite promising findings, the consensus on metformin's application in GC prevention and treatment necessitates further clinical and mechanistic studies to confirm its therapeutic role.
A total review of metformin use during pregnancy compared to [[insulin]] alone found good short-term safety for both the mother and baby, but unclear long-term safety. Several [[observational study|observational studies]] and randomized controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes. Nonetheless, several concerns have been raised and evidence on the long-term safety of metformin for both mother and child is lacking. Compared with insulin, women with gestational diabetes treated with metformin gain less weight and are less likely to develop pre‐eclampsia during pregnancy. Babies born to women treated with metformin have less [[visceral fat]], and this may make them less prone to insulin resistance in later life. The use of metformin for gestational diabetes resulted in smaller babies compared to treatment with insulin. However, despite initially lower birth weight, children exposed to metformin during pregnancy had accelerated growth after birth, and were heavier by mid-childhood than those exposed to insulin during pregnancy. This pattern of initial low birth weight followed by catch-up growth that surpasses comparative children has been associated with long-term cardiometabolic disease.
Metformin use is typically associated with weight loss. It appears to be safe and effective in counteracting the weight gain caused by the [[antipsychotic]] medications [[olanzapine]] and [[clozapine]]. Although modest reversal of clozapine-associated weight gain is found with metformin, primary prevention of weight gain is more valuable.
There is some evidence metformin may be helpful in extending lifespan, even in otherwise healthy people. It has received substantial interest as an agent that delays aging, possibly through similar mechanisms as its treatment of diabetes (insulin and carbohydrate regulation).
Preliminary studies have examined whether metformin can reduce the risk of [[Alzheimer's disease]], and whether there is a correlation between type{{nbsp}}2 diabetes and risk of Alzheimer's disease.
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== 禁忌事項 ==
== Contraindications ==
{{Anchor|Contraindications}}
Metformin is [[contraindication|contraindicated]] in people with:
The most common [[adverse drug reaction|adverse effect]] of metformin is gastrointestinal irritation, including [[diarrhea]], cramps, nausea, vomiting, and increased [[flatulence]]. Metformin is more commonly associated with gastrointestinal adverse effects than most other antidiabetic medications. The most serious potential adverse effect of metformin is [[lactic acidosis]]; this complication is rare, and seems to be related to impaired liver or kidney function. Metformin is not approved for use in those with severe kidney disease, but may still be used at lower doses in those with kidney problems.
メトホルミンの最も一般的な[[adverse drug reaction/ja|副作用]]は、[[diarrhea/ja|下痢]]、けいれん、吐き気、嘔吐、および[[flatulence/ja|鼓腸]]の増加などの消化管刺激である。メトホルミンは、他のほとんどの抗糖尿病医薬品よりも一般的に消化器系の副作用と関連している。メトホルミンの最も重篤な潜在的副作用は[[lactic acidosis/ja|乳酸アシドーシス]]である；この合併症はまれであり、肝機能または腎機能の低下に関連しているようである。メトホルミンは重度の腎臓病患者への使用は承認されていないが、腎臓に問題のある患者には低用量で使用することができる。
Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1.0 to 1.7 g/day) and increasing the dose gradually, but even with low doses, 5% of people may be unable to tolerate metformin. Use of slow or extended-release preparations may improve tolerability.
Long-term use of metformin has been associated with increased [[homocysteine]] levels and [[malabsorption]] of [[cyanocobalamin|vitamin B<sub>12</sub>]]. Higher doses and prolonged use are associated with increased incidence of [[Vitamin B12 deficiency|vitamin B<sub>12</sub> deficiency]], and some researchers recommend screening or prevention strategies.
Lactic acidosis almost never occurs with metformin exposure during routine medical care. Rates of metformin-associated lactic acidosis are about nine per 100,000 persons/year, which is similar to the background rate of lactic acidosis in the general population. A systematic review concluded no data exists to definitively link metformin to lactic acidosis.
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メトホルミンは一般に軽度から中等度の慢性腎臓病において安全であり、[[estimated glomerular filtration rate/ja|推算糸球体濾過量]]（eGFR）の重症度に応じてメトホルミンの投与量を比例的に減量し、腎機能を定期的に評価する（例えば、定期的な血漿クレアチニン測定）。米国[[Food and Drug Administration/ja|食品医薬品局]]（FDA）は、eGFRのカットオフ値である30mL/分/1.73m<sup>2</sup>未満の、より重症の慢性腎臓病ではメトホルミンの使用を避けるよう推奨している。乳酸は肝[[gluconeogenesis/ja|糖新生]]の[[Substrate (biochemistry)/ja|基質]]であり、メトホルミンが阻害するプロセスであるため、メトホルミンの使用により肝臓での乳酸取り込みが減少する。健常者では、このわずかな過剰は他の機序（障害のない腎臓による取り込みを含む）によって排出され、乳酸の血中濃度の有意な上昇は起こらない。腎機能が著しく低下している場合は、メトホルミンと乳酸のクリアランスが低下し、両方の濃度が上昇し、乳酸が蓄積する可能性がある。メトホルミンは乳酸の肝臓への取り込みを減少させるため、乳酸アシドーシスを誘発するような病態は禁忌である。一般的な原因としては、[[alcoholism/ja|アルコール中毒]]（[[nicotinamide adenine dinucleotide/ja|NAD+]]貯蔵量の枯渇による）、心不全、呼吸器疾患（組織の酸素化が不十分なため）などが挙げられる；最も一般的な原因は腎疾患である。
Metformin is generally safe in people with mild to moderate chronic kidney disease, with proportional reduction of metformin dose according to severity of [[estimated glomerular filtration rate]] (eGFR) and with periodic assessment of kidney function, (e.g., periodic plasma creatinine measurement). The US [[Food and Drug Administration]] (FDA) recommends avoiding the use of metformin in more severe chronic kidney disease, below the eGFR cutoff of 30 mL/minute/1.73 m<sup>2</sup>. Lactate uptake by the liver is diminished with metformin use because lactate is a [[Substrate (biochemistry)|substrate]] for hepatic [[gluconeogenesis]], a process that metformin inhibits. In healthy individuals, this slight excess is cleared by other mechanisms (including uptake by unimpaired kidneys), and no significant elevation in blood levels of lactate occurs. Given severely impaired kidney function, clearance of metformin and lactate is reduced, increasing levels of both, and possibly causing lactic acid buildup. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication. Common causes include [[alcoholism]] (due to depletion of [[nicotinamide adenine dinucleotide|NAD+]] stores), heart failure, and respiratory disease (due to inadequate tissue oxygenation); the most common cause is kidney disease.
Metformin-associated lactate production may also take place in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors. The clinical significance of this is unknown, though, and the risk of metformin-associated lactic acidosis is most commonly attributed to decreased hepatic uptake rather than increased intestinal production
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=== 過剰摂取===
=== Overdose ===
過量投与後の最も一般的な症状としては、嘔吐、[[diarrhea/ja|下痢]]、腹痛、[[tachyardia/ja|頻脈]]、眠気、まれに[[hypoglycemia/ja|低血糖]]または[[hyperglycemia/ja|高血糖]]がある。メトホルミン過剰摂取の治療は、特異的な解毒剤が知られていないため、一般に支持療法である。重度の過量投与では、体外治療が推奨される。メトホルミンは[[molecular weight/ja|分子量]]が低く、[[plasma protein binding/ja|血漿蛋白結合]]がないため、これらの手技にはメトホルミンを[[blood plasma/ja|血漿]]から除去し、さらなる乳酸の過剰産生を防ぐという利点がある。
The most common symptoms following an overdose include vomiting, [[diarrhea]], abdominal pain, [[tachycardia]], drowsiness, and rarely, [[hypoglycemia]] or [[hyperglycemia]]. Treatment of metformin overdose is generally supportive, as no specific antidote is known. Extracorporeal treatments are recommended in severe overdoses. Due to metformin's low [[molecular weight]] and lack of [[plasma protein binding]], these techniques have the benefit of removing metformin from the [[blood plasma]], preventing further lactate overproduction.
Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or to assist in a forensic death investigation. Blood or plasma metformin concentrations are usually in a range of 1–4 mg/L in persons receiving therapeutic doses, 40–120 mg/L in victims of acute overdosage, and 80–200 mg/L in fatalities. Chromatographic techniques are commonly employed.
The risk of metformin-associated lactic acidosis is also increased by a massive overdose of metformin, although even quite large doses are often not fatal.
The [[H2 antagonist|H<sub>2</sub>-receptor antagonist]] [[cimetidine]] causes an increase in the plasma concentration of metformin by reducing [[clearance (medicine)|clearance]] of metformin by the kidneys; both metformin and cimetidine are cleared from the body by [[Renal physiology#Secretion|tubular secretion]], and both, particularly the [[cation]]ic (positively [[electric charge|charged]]) form of cimetidine, may compete for the same transport mechanism. A small [[blind experiment|double-blind]], randomized study found the [[antibiotic]] [[cephalexin]] to also increase metformin concentrations by a similar mechanism; theoretically, other cationic medications may produce the same effect.
Metformin also interacts with [[anticholinergic]] medications, due to their effect on gastric motility. Anticholinergic drugs reduce gastric motility, prolonging the time drugs spend in the [[gastrointestinal tract]]. This impairment may lead to more metformin being absorbed than without the presence of an anticholinergic drug, thereby increasing the concentration of metformin in the plasma and increasing the risk for adverse effects.
The molecular mechanism of metformin is not completely understood. Multiple potential mechanisms of action have been proposed: inhibition of the mitochondrial respiratory chain ([[Respiratory complex I|complex I]]), activation of [[AMP-activated protein kinase]] (AMPK), inhibition of glucagon-induced elevation of [[cyclic adenosine monophosphate]] (cAMP) with reduced activation of [[protein kinase A]] (PKA), complex IV–mediated inhibition of the GPD2 variant of mitochondrial [[Glycerol-3-phosphate dehydrogenase#GPD2|glycerol-3-phosphate dehydrogenase]] (thereby reducing glycerol-derived hepatic gluconeogenesis), and an effect on [[gut flora|gut microbiota]].
Metformin exerts an anorexiant effect in most people, decreasing caloric intake. Metformin decreases [[gluconeogenesis]] (glucose production) in the liver. Metformin inhibits basal secretion from the [[pituitary gland]] of [[growth hormone]], [[adrenocorticotropic hormone]], [[follicle stimulating hormone]], and expression of [[proopiomelanocortin]], which in part accounts for its insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovaries. The average patient with type{{nbsp}}2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.
Activation of AMPK was required for metformin's inhibitory effect on liver glucose production. AMPK is an enzyme that plays an important role in insulin signaling, whole-body energy balance, and the metabolism of glucose and [[lipid|fats]]. AMPK activation is required for an increase in the expression of [[small heterodimer partner]], which in turn inhibited the [[gene expression|expression]] of the hepatic gluconeogenic genes [[phosphoenolpyruvate carboxykinase]] and [[glucose 6-phosphatase]]. Metformin is frequently used in research along with [[AICA ribonucleotide]] as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain: metformin increases the concentration of [[cytosol]]ic [[adenosine monophosphate]] (AMP) (as opposed to a change in total AMP or total AMP/[[adenosine triphosphate]]) which could activate AMPK allosterically at high levels; a newer theory involves binding to [[PEN-2]]. Metformin inhibits cyclic AMP production, blocking the action of [[glucagon]], and thereby reducing fasting glucose levels. Metformin also induces a profound shift in the faecal microbial community profile in diabetic mice, and this may contribute to its mode of action possibly through an effect on [[glucagon-like peptide-1]] secretion.
In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral [[glucose uptake]] (by inducing the phosphorylation of [[GLUT4]] enhancer factor), decreases insulin-induced suppression of [[fatty acid metabolism|fatty acid oxidation]], and decreases the absorption of glucose from the [[gastrointestinal tract]]. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors. The increase in insulin binding after metformin treatment has also been demonstrated in patients with type{{nbsp}}2 diabetes.
AMPK probably also plays a role in increased peripheral insulin sensitivity, as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms, however AMPK likely has a modest overall effect and its activity is not likely to directly decrease gluconeogenesis in the liver.
Metformin has indirect [[antiandrogen]]ic effects in women with [[insulin resistance]], such as those with PCOS, due to its beneficial effects on insulin sensitivity. It may reduce [[testosterone]] levels in such women by as much as 50%. A [[Cochrane review]], though, found that metformin was only slightly effective for decreasing androgen levels in women with PCOS.
Metformin also has significant effects on the gut microbiome, such as its effect on increasing [[agmatine]] production by gut bacteria, but the relative importance of this mechanism compared to other mechanisms is uncertain.
Due to its effect on GLUT4 and AMPK, metformin has been described as an [[exercise mimetic]].
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=== 薬物動態 ===
=== Pharmacokinetics ===
メトホルミンの経口[[bioavailability/ja|生物学的利用能]]は、[[fasting/ja|空腹]]条件下で50～60％であり、ゆっくりと吸収される。血漿中濃度のピーク（C<sub>max</sub>）は、メトホルミンの即時放出型製剤では服用後1～3時間以内に、徐放型製剤では4～8時間以内に到達する。メトホルミンの[[plasma protein binding/ja|血漿タンパク質結合]]は、非常に高い[[volume of distributino/ja|見かけの分布容積]]（単回投与で300～1000 L）に反映されるように、無視できる。[[Steady state/ja|定常状態]]は通常1～2日で到達する。
Metformin has an oral [[bioavailability]] of 50–60% under [[fasting]] conditions, and is absorbed slowly. Peak plasma concentrations (C<sub>max</sub>) are reached within 1–3 hours of taking immediate-release metformin and 4–8 hours with extended-release formulations. The [[plasma protein binding]] of metformin is negligible, as reflected by its very high [[volume of distribution|apparent volume of distribution]] (300–1000 L after a single dose). [[Steady state]] is usually reached in 1–2 days.
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メトホルミンの酸解離定数（pK<sub>a</sub>）は2.8と11.5であるため、生理的pH値では非常に大部分が親水性の陽イオン種として存在する。メトホルミンのpK<sub>a</sub>値は、血中非イオン化率0.01％未満の他のほとんどの塩基性医薬品よりも強い塩基となる。さらに、非イオン化種の[[Lipophilicity/ja|脂溶性]]は、-1.43という低いlogP値（オクタノールと水の間の非イオン化型の分配係数のlog(10)）が示すようにわずかである。これらの化学的パラメータは、親油性が低いことを示しており、その結果、メトホルミンが細胞膜を通過して急速に受動拡散する可能性は低い。脂溶性が低いため、[[Membrane transport protein/ja|トランスポーター]]が必要である。メトホルミンが細胞内に入るためには、[[SLC22A1/ja|SLC22A1]]が必要である。メトホルミンのlogPは[[phenformin/ja|フェンホルミン]]のlogP（-0.84）よりも小さいが、これはメトホルミンの2つのメチル置換基が[[phenformin/ja|フェンホルミン]]の大きなフェニルエチル側鎖よりも低い親油性を与えるためである。現在，メトホルミンよりも優れた経口吸収性を有するプロドラッグを製造する目的で，メトホルミンのより親油性の誘導体が研究されている。
Metformin has acid dissociation constant values (pK<sub>a</sub>) of 2.8 and 11.5, so it exists very largely as the hydrophilic cationic species at physiological pH values. The metformin pK<sub>a</sub> values make it a stronger base than most other basic medications with less than 0.01% nonionized in blood. Furthermore, the [[Lipophilicity|lipid solubility]] of the nonionized species is slight as shown by its low logP value (log(10) of the distribution coefficient of the nonionized form between octanol and water) of −1.43. These chemical parameters indicate low lipophilicity and, consequently, rapid passive diffusion of metformin through cell membranes is unlikely. As a result of its low lipid solubility it requires the [[Membrane transport protein|transporter]] [[SLC22A1]] in order for it to enter cells. The logP of metformin is less than that of [[phenformin]] (−0.84) because two methyl substituents on metformin impart lesser lipophilicity than the larger phenylethyl side chain in [[phenformin]]. More lipophilic derivatives of metformin are presently under investigation with the aim of producing prodrugs with superior oral absorption than metformin.
Metformin is not [[drug metabolism|metabolized]]. It is [[clearance (medicine)|cleared]] from the body by [[renal physiology#Secretion|tubular secretion]] and excreted unchanged in the urine; it is undetectable in blood plasma within 24 hours of a single oral dose. The average [[biological half-life|elimination half-life]] in plasma is 6.2 hours. Metformin is distributed to (and appears to accumulate in) [[red blood cell]]s, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).
Some evidence indicates that liver concentrations of metformin in humans may be two to three times higher than plasma concentrations, due to [[portal vein]] absorption and first-pass uptake by the liver in oral administration.
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== 化学 ==
== Chemistry ==
{{Anchor|Chemistry}}
Metformin hydrochloride (1,1-dimethylbiguanide hydrochloride) is freely soluble in water, slightly soluble in ethanol, but almost insoluble in acetone, ether, or chloroform. The pK<sub>a</sub> of metformin is 12.4. The usual [[chemical synthesis|synthesis]] of metformin, originally described in 1922, involves the one-pot reaction of [[dimethylamine]] [[hydrochloride]] and [[2-cyanoguanidine]] over heat.
According to the procedure described in the 1975 Aron patent, and the ''Pharmaceutical Manufacturing Encyclopedia'', [[equivalent weight|equimolar]] amounts of dimethylamine and 2-cyanoguanidine are dissolved in [[toluene]] with cooling to make a [[Concentration#Qualitative description|concentrated]] solution, and an equimolar amount of [[hydrogen chloride]] is slowly added. The mixture begins to boil on its own, and after cooling, metformin hydrochloride [[precipitate]]s with a 96% [[Yield (chemistry)|yield]].
The [[biguanide]] class of antidiabetic medications, which also includes the withdrawn agents [[phenformin]] and [[buformin]], originates from the [[Galega officinalis|French lilac]] or goat's rue (''Galega officinalis''), a plant used in folk medicine for several centuries. ''G. officinalis'' itself does not contain any of these medications, but [[Galegine|isoamylene guanidine]]; phenformin, buformin, and metformin are chemically synthesized compounds composed of two guanidine molecules, and are more [[lipophilic]] than the plant-derived parent compound.
Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell, as a product in the synthesis of ''N'',''N''-dimethylguanidine. In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied. This result was ignored, as other [[guanidine]] analogs such as the [[synthalin]]s, took over and were themselves soon overshadowed by insulin.
Interest in metformin resumed at the end of the 1940s. In 1950, metformin, unlike some other similar compounds, was found not to decrease [[blood pressure]] and [[heart rate]] in animals. That year, Filipino physician Eusebio Y. Garcia used metformin (he named it Fluamine) to treat influenza; he noted the medication "lowered the blood sugar to minimum physiological limit" and was not toxic. Garcia believed metformin to have [[bacteriostatic]], [[Antiviral drug|antiviral]], [[antimalarial]], [[antipyretic]], and [[analgesic]] actions. In a series of articles in 1954, Polish pharmacologist Janusz Supniewski was unable to confirm most of these effects, including lowered blood sugar. Instead he observed antiviral effects in humans.
French diabetologist Jean Sterne studied the antihyperglycemic properties of [[galegine]], an [[alkaloid]] isolated from ''G. officinalis'', which is related in structure to metformin, and had seen brief use as an antidiabetic before the synthalins were developed. Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to reinvestigate the blood sugar-lowering activity of metformin and several biguanide analogs. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" (glucose eater) for the medication and published his results in 1957.
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メトホルミンは1958年に[[:en:British National Formulary|British National Formulary]]で入手できるようになった。イギリスではロナという小さなアロンの子会社が販売していた。
Metformin became available in the [[British National Formulary]] in 1958. It was sold in the UK by a small Aron subsidiary called Rona.
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メトホルミンに対する幅広い関心が再燃したのは、1970年代に他のビグアナイド薬が撤退してからであった。メトホルミンは1972年にカナダで承認されたが、2型糖尿病に対する米国[[Food and Drug Administration/ja|食品医薬品局]]（FDA）の承認は1994年まで得られなかった。グルコファージは[[Bristol-Myers Squibb]]によってライセンス生産され、1995年3月3日から米国で販売されたメトホルミンの最初のブランド製剤である。[[generic drug/ja|ジェネリック]]製剤は、いくつもの国で入手可能であり、メトホルミンは、世界で最も広く処方されている抗糖尿病医薬品になったと考えられている。
Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972, but did not receive approval by the U.S. [[Food and Drug Administration]] (FDA) for type{{nbsp}}2 diabetes until 1994. Produced under license by [[Bristol-Myers Squibb]], Glucophage was the first branded formulation of metformin to be marketed in the U.S., beginning on 3 March 1995. [[generic drug|Generic]] formulations are available in several countries, and metformin is believed to have become the world's most widely prescribed antidiabetic medication.
Metformin and its major transformation product guanylurea are present in [[wastewater treatment plant]] effluents and regularly detected in surface waters. Guanylurea concentrations above 200 μg/L have been measured in the German river [[Erpe (Spree)|Erpe]], which are amongst the highest reported for pharmaceutical transformation products in aquatic environments.
[[File:Metformin 500mg Tablets.jpg|thumb|right|Generic metformin 500-mg tablets, as sold in the United Kingdom]]
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"メトホルミン"という名称は、この医薬品の[[:en:British Approved Name|BAN]]、[[:en:United States Adopted Name|USAN]]、[[:en:International Nonproprietary Name|INN]]であり、いくつかの[[trade name/ja|商品名]]で販売されている。一般的な商品名には、米国ではグルコファージ、リオメット、フォルタメット、グルメッツァなどがある。世界の他の地域では、Obimet、Gluformin、Dianben、Diabex、Diaformin、Metsol、Siofor、Metfogamma、Gliforもある。市販されているメトホルミンにはいくつかの製剤があり、液剤以外はすべて同等のジェネリック医薬品がある。メトホルミンIR（即時放出）には500mg、850mg、1000mgの錠剤があり、メトホルミンXR（徐放）には500mg、750mg、1000mgの錠剤がある（米国ではFortamet、Glumetza、Glucophage XRとしても販売されている）。また、液体メトホルミン（米国ではリオメットとして販売）もあり、5 mLの溶液に500mgの錠剤と同量の薬物が含まれている。
The name "Metformin" is the [[British Approved Name|BAN]], [[United States Adopted Name|USAN]], and [[International Nonproprietary Name|INN]] for this medication, and is sold under several [[trade name]]s. Common brand names include Glucophage, Riomet, Fortamet, and Glumetza in the US. In other areas of the world, there is also Obimet, Gluformin, Dianben, Diabex, Diaformin, Metsol, Siofor, Metfogamma and Glifor. There are several formulations of Metformin available to the market, and all but the liquid form have generic equivalents. Metformin IR (immediate release) is available in 500-, 850-, and 1000-mg tablets, while Metformin XR (extended release) is available in 500-, 750-, and 1000-mg strengths (also sold as Fortamet, Glumetza, and Glucophage XR in the US). Also available is liquid metformin (sold as Riomet in the US), where 5 mL of solution contains the same amount of drug as a 500-mg tablet.
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==== 他の医薬品との併用 ====
==== Combination with other medications ====
2型糖尿病に用いる場合、メトホルミンはしばしば他の医薬品と併用処方される。
When used for type{{nbsp}}2 diabetes, metformin is often prescribed in combination with other medications.
A combination of metformin and [[rosiglitazone]] was released in 2002, and sold as Avandamet by [[GlaxoSmithKline]], or as a generic medication. Formulations are 500/1, 500/2, 500/4, 1000/2, and 1000 mg/4 mg of metformin/rosiglitazone.
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2009年までには、最も人気のあるメトホルミン配合剤となった。
By 2009, it had become the most popular metformin combination.
In 2005, the stock of Avandamet was removed from the market, after inspections showed the factory where it was produced was violating [[good manufacturing practice]]s. The medication pair continued to be prescribed separately, and Avandamet was again available by the end of that year. A generic formulation of metformin/rosiglitazone from [[Teva Pharmaceutical Industries|Teva]] received tentative approval from the FDA and reached the market in early 2012.
However, following a meta-analysis in 2007 that linked the medication's use to an increased risk of [[Myocardial infarction|heart attack]], concerns were raised over the safety of medicines containing rosiglitazone. In September 2010, the [[European Medicines Agency]] recommended that the medication be suspended from the European market because the benefits of rosiglitazone no longer outweighed the risks.
It was withdrawn from the market in the UK and India in 2010, and in New Zealand and South Africa in 2011. did not allow rosiglitazone or metformin/rosiglitazone to be sold without a prescription; moreover, makers were required to notify patients of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies.
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2013年11月、FDAは2009年に実施されたRECORD臨床試験（6年間の非盲検[[randomized control trial/ja|無作為化対照試験]]）の結果を検討した結果、ロシグリタゾンに対する以前の制限を解除した。
In November 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the 2009 RECORD clinical trial (a six-year, open-label [[randomized control trial]]), which failed to show elevated risk of heart attack or death associated with the medication.
The combination of [[Pioglitazone/metformin|metformin and pioglitazone]] (Actoplus Met, Piomet, Politor, Glubrava) is available in the US and the European Union.
DPP-4 inhibitors combined with metformin include a [[sitagliptin/metformin]] combination (Janumet), a [[saxagliptin/metformin]] combination (Kombiglyze XR, Komboglyze), and an [[alogliptin/metformin]] combination (Kazano, Vipdomet).
[[Linagliptin]] combined with metformin hydrochloride is sold under the brand name Jentadueto. As of August 2021, linagliptin/metformin is available as a [[generic medicine]] in the US.
There are combinations of metformin with the [[SGLT-2 inhibitor]]s [[Dapagliflozin/metformin|dapagliflozin]], [[Empagliflozin/metformin|empagliflozin]], and [[Canagliflozin/metformin|canagliflozin]].
A 2019 systematic review suggested that there is limited evidence if the combined used of metformin with sulfonylurea compared to the combination of metformin plus another glucose-lowering intervention, provides benefit or harm in mortality, severe adverse events, macrovascular and microvascular complications. Combined metformin and sulfonylurea therapy did appear to lead to higher risk of hypoglicaemia.
Metformin is available combined with the sulfonylureas [[glipizide]] (Metaglip) and [[glibenclamide]] (US: glyburide) (Glucovance). Generic formulations of metformin/glipizide and metformin/glibenclamide are available (the latter is more popular).
[[Meglitinide]]s are similar to sulfonylureas, as they bind to beta cells in the pancreas, but differ by the site of binding to the intended receptor and the drugs' affinities to the receptor. As a result, they have a shorter duration of action compared to sulfonylureas, and require higher blood glucose levels to begin to secrete insulin. Both meglitinides, known as nateglinide and repanglinide, is sold in formulations combined with metformin. A [[repaglinide]]/metformin combination is sold as Prandimet, or as its generic equivalent.
The combination of metformin with [[pioglitazone]] and glibenclamide is available in India as Accuglim-MP, Adglim MP, and Alnamet-GP, along with the Philippines as Tri-Senza.
In December 2019, the US FDA announced that it learned that some metformin medicines manufactured outside the United States might contain a nitrosamine impurity called [[N-nitrosodimethylamine]] (NDMA), classified as a probable human carcinogen, at low levels. Health Canada announced that it was assessing NDMA levels in metformin.
In February 2020, [[Health Canada]] announced a recall of Apotex immediate-release metformin, followed in March by recalls of Ranbaxy metformin and in March by Jamp metformin.
In May 2020, the FDA asked five companies to voluntarily recall their [[sustained-release]] metformin products. The five companies were not named, but they were revealed to be Amneal Pharmaceuticals, Actavis Pharma, Apotex Corp, Lupin Pharma, and Marksans Pharma Limited in a letter sent to [[Valisure]], the pharmacy that had first alerted the FDA to this contaminant in metformin via a Citizen Petition.
In June 2020, the FDA posted its laboratory results showing NDMA amounts in metformin products it tested. It found NDMA in certain lots of ER metformin, and is recommending companies recall lots with levels of NDMA above the acceptable intake limit of 96 nanograms per day. The FDA is also collaborating with international regulators to share testing results for metformin.
In July 2020, Lupin Pharmaceuticals pulled all [[Lot number|lots]] (batches) of metformin after discovering unacceptably high levels of NDMA in tested samples.
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2020年8月、Bayshore Pharmaceuticals社は2つのロットの錠剤を回収した。
In August 2020, Bayshore Pharmaceuticals recalled two lots of tablets.
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== 研究 ==
== Research ==
{{Anchor|Research}}
Metformin has been studied for its effects on multiple other conditions, including:
* [[Cardiovascular disease]] in people with diabetes
* 糖尿病患者における[[Cardiovascular disease/ja|心臓血管疾患]]
* [[Ageing|Aging]]
* [[Ageing/ja|老化]]
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メトホルミンは[[fragile X syndrome/ja|脆弱X症候群]]の人の体重を減らすかもしれないが、神経症状や精神症状を改善するかどうかは不明である。メトホルミンは生体内（''[[Caenorhabditis elegans/ja|線虫]]''および[[Acheta domesticus/ja|コオロギ]]）で老化に対する影響について研究されている。2017年のレビューによると、メトホルミンを服用している糖尿病患者は全死亡率が低かった。また、他の治療を受けている人に比べて、がんや心血管疾患も減少していた。
While metformin may reduce body weight in persons with [[fragile X syndrome]], whether it improves neurological or psychiatric symptoms is uncertain. Metformin has been studied in vivo (''[[Caenorhabditis elegans|C. elegans]]'' and [[Acheta domesticus|crickets]]) for effects on aging. A 2017 review found that people with diabetes who were taking metformin had lower all-cause mortality. They also had reduced cancer and cardiovascular disease compared with those on other therapies.
There is also some research suggesting that although metformin prevents diabetes, it does not reduce the risk of cancer and cardiovascular disease and thus does not extend lifespan in non-diabetic individuals. Furthermore, some studies suggest that long-term chronic use of metformin by healthy individuals may develop [[vitamin B12 deficiency]].
Markowicz-Piasecka M, Huttunen KM, Mateusiak L, Mikiciuk-Olasik E, Sikora J (2017). "Is Metformin a Perfect Drug? Updates in Pharmacokinetics and Pharmacodynamics". Current Pharmaceutical Design. 23 (17): 2532–2550. doi:10.2174/1381612822666161201152941. PMID27908266.
Zhou T, Xu X, Du M, Zhao T, Wang J (October 2018). "A preclinical overview of metformin for the treatment of type 2 diabetes". Biomedicine & Pharmacotherapy. 106: 1227–1235. doi:10.1016/j.biopha.2018.07.085. PMID30119191. S2CID52031602.
