Metformin plasma levels

Memantine is not a major substrate for hepatic cytochrome P450 isoenzymes and has not been shown to significantly inhibit or induce these enzymes. However, memantine is partially excreted by renal tubular secretion. Thus, concomitant use of other medications that use the same renal system (i.e., triampterene, hydrochlorothiazide, digoxin, cimetidine, ranitidine, metformin, and quinidine) may affect plasma levels of both drugs (Namenda 2005). Memantine should not be used in combination with other NMDA receptor antagonists, such as amantadine or dextromethorphan, because these combinations have not been formally studied. The clearance of memantine can be reduced when the urine is alkalinized, such as with the concomitant use of sodium bicarbonate or carbonic anhy-... 

METFORMIN NS AIDS Possibility oft plasma levels of metformin if there is renal impairment due to NSAIDs. Phenylbutazone is likely to i renal elimination of metformin and t plasma levels. 

Topiramate may increase plasma levels of metformin also, metformin may reduce clearance of topiramate and increase topiramate levels... 

Metformin has an absolute oral bioavailability of about 50-60% of the dose after oral application of a single dose. Deconvolution analysis showed that after a short lag-time, the available remainder of the oral dose was absorbed at an exponential rate over about 6 h (Tucker et al., 1981). The bioavailability of phenformin seems to be more variable but also in the range of about 50% (Beckmann, 1968 Travis and Sayers, 1970). In general, absorption of biguanides is slower than their elimination, hence the plasma levels follow flip-flop kinetics (Pentikainen et al., 1979). 

For a review, see Sachse etal. (1982). Combining acarbose with sulphonylurea or metformin or insulin may lead to hypoglycaemia, although acarbose itself will not produce hypoglycaemia (doses have to be corrected). The effect of acarbose may be reduced by antacids, cholestyramine, pancreatic enzymes and adsorbants. Plasma levels of vitamin B6 increased, and vitamin A concentrations decreased with acarbose (Couet et al., 1989). 

Another study in 19 diabetic patients given acarbose 50 or 100 mg three times daily and metformin 500 mg twice daily, also found that acarbose lowered metformin levels (AUC reduced by 12 to 13%, maximum plasma levels reduced by 17 to 20%). Nevertheless, the drug combination reduced the postprandial glucose concentration at 3 hours by 15% mote than metformin alone. Similarly, the manufacturer notes that, in a study in healthy subjects, miglitol 100 mg three times daily for 7 days reduced the AUC and maximum level of a single 1-g dose of metformin by 12% and 13%, respectively, although this difference was not statistically significant. ... 

Metformin is the only biguanide available in the United States. It enhances insulin sensitivity of both hepatic and peripheral (muscle) tissues. This allows for increased uptake of glucose into these insulin-sensitive tissues. Metformin consistently reduces A1C levels by 1.5% to 2%, FPG levels by 60 to 80 mg/dL, and retains the ability to reduce FPG levels when they are very high (>300 mg/dL). It reduces plasma triglycerides and low-density lipoprotein (LDL) cholesterol by 8% to 15% and modestly increases high-density lipoprotein (HDL) cholesterol (2%). It does not induce hypoglycemia when used alone. 

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explained by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. 

Diabetes mellitus, combination therapy PO With insulin Initially, 15-30 mg once a day. Initially, continue current insulin dosage then decrease insulin dosage by 10% to 25% if hypoglycemia occurs or plasma glucose level decreases to less than 100 mg/dl. Maximum 45 mg/day. With sulfonylureas Initially, 15-30 mg/day. Decrease sulfonylurea dosage if hypoglycemia occurs. With metformin Initially, 15-30 mg/day. As monotherapy Monotherapy is not to be used if patient is well controlled with diet and exercise alone. Initially, 15-30 mg/day. May increase dosage in increments until 45 mg/day is reached. 

Lalau JD, Race JM. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999 20(4) 377-84. 

The SNAC/heparin combination has been evaluated in phase I and phase II clinical trials. Furthermore, in phase I clinical trials dosing insulin in combination with SNAC a rapid elevation of plasma insulin and a subsequent decrease in plasma glucose levels were observed. In a phase II clinical trial in patients with type 2 diabetes, insulin was orally administered in combination with SNAC and metformin failing to achieve significant superior glycemic control over treatment with metformin alone (Hoffman and Qadri 2008). 

Rouru et al. (1992) investigated in genetically obese male Zucker rats the effect of subchronic metformin treatment on food intake, weight gain and plasma insulin and corticosterone levels and somatostatin concentrations in the pancreas. 

Kidney failure requires special attention because of metformin accumulation. Severe lactacidotic coma despite normal renal function has been reported in a 35-year-old diabetic man taking metformin and alcohol (Ryder, 1984). While fasting plasma lactate concentrations remained unaltered after metformin, a rise was noted in response to meals (from 1.4 0.1 to 1.8 0.2 mM) (Pedersen et al., 1989). Arterial blood gas analysis in one case revealed a pH of 6.76 and a bicarbonate level of 1.6 mM before treatment of lactacidosis. After therapy, which included oxygen, volume expansion and haemodialysis, the patient completely recovered (Gan et al., 1992). 

Metformin used as monotherapy reduced plasma glucose levels in normal-weight Type-II diabetics considerably (172 to 103 mg per 100 ml), whereas serum insulin was unchanged over a 3 month period (Jackson et al., 1987). The hypoglycaemic action of metformin became fully effective within 2-3 weeks of treatment. Clinical studies point out that gastrointestinal side effects can be avoided if medication is started slowly and taken postprandially (Fig. 25). 

Intravenous administration of 7-ketocholesterol decreased the uptake of cholesterol into rabbit aorta.75 5a-Cholest-8(14)-en-38-ol-15-one suppressed serum cholesterol levels and hepatic cholesterol synthesis. 6 S-8527 significantly reduced serum cholesterol by inhibiting the hepatic synthesis of lipoprotein fractions carrying cholesterol.77 Metformin produced only a slight reduction of plasma cholesterol levels in rabbits fed a high cholesterol diet. However, it markedly decreased aortic cholesterol esters and the atheromatous process, with a simultaneous change in the composition of VLDL.78 79... 

Consideration should be given to stopping treatment with metformin if the plasma lactate level exceeds 3 mM or in the setting of decreased renal or hepatic function. It also is prudent to stop metformin if a patient is undergoing a prolonged fast or is treated with a very low calorie diet. Myocardial infarction or septicemia mandates immediate drug discontinuation. 

---