Pharmacokinetic Parameters Of Metformin Research Articles

Effects of Catha edulis (Khat) on the Pharmacokinetics of Metformin in Diabetic Rats Using UPLC/MS/MS Analysis and Its Impact on Hepatic CYP450 Enzymes

Catha edulis Forsk., commonly known as Khat, is a stimulant plant that is chewed in the Horn of Africa and the southern regions of the Arabian Peninsula. It is often used alongside conventional drugs, but there is a lack of research on its interactions with other drugs. In this study, our aim was to investigate the possibility of an herb–drug interaction between KT extract and metformin (MT) by exploring the effect of KT on the in vivo pharmacokinetics of MT in diabetic Wistar albino rats and monitoring blood glucose levels through time intervals, comparing when MT was given alone and co-administered with KT. Rats were given 500 mg/kg of KT extract and 300 mg/kg of MT daily for 7 days. The pharmacokinetic parameters of MT were analyzed using UPLC-MS/MS. The quantification was conducted using multiple reaction monitoring (MRM) in positive ion mode. The transitions used were (m/z) 130.006→59.939 for MT and 260.125→116.018 for propranolol as an internal standard (IS). An Acquity UPLC BEH HSS T3 C18 column was used with isocratic elution, and the mobile phase was formic acid (0.1%): acetonitrile (70:30 v/v) at a flow rate of 0.25 mL/min. In addition, the study delved into the in vitro impact of KT on the CYP3A4 enzyme, seeking to identify any potential disruptions in MT’s metabolism that could alter its pharmacokinetics. The effect of KT extract on CYP3A4 enzyme activity was investigated using fluorescence-based enzyme assays and a CYP3A4 Inhibitor Screening Kit. The results indicated that the combined treatment showed increased systemic exposure to MT, with Cmax and AUC levels increasing by 33.42% and 45.23%, respectively. Additionally, the combination treatment led to significantly lower fasting blood glucose (FBG) levels compared to the groups treated with MT alone. It was found that at a concentration of 500 µg/mL, the CYP3A4 enzyme activity was maximally suppressed by approximately 57%, while at 250 µg/mL, it was inhibited by almost 50%. In comparison, the standard Ketoconazole only inhibited CYP3A4 activity by approximately 58%. Therefore, the in vitro results suggest that KT extract has the potential to affect CYP3A4 activity at high doses. In conclusion, the combination treatment resulted in a significant increase in MT’s blood sugar-lowering effects. Therefore, it is important to be aware of this potential interaction and to monitor blood sugar levels closely when using KT alongside MT.

Identification of Transporter Polymorphisms Influencing Metformin Pharmacokinetics in Healthy Volunteers

For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we conducted our study on healthy participants. This is the first investigation to consider demographic characteristics alongside all transporters involved in metformin distribution. Pharmacokinetic parameters of metformin were found to be affected by age, sex, ethnicity, and several polymorphisms. Age and SLC22A4 and SLC47A2 polymorphisms affected the area under the concentration-time curve (AUC). However, after adjusting for dose-to-weight ratio (dW), sex, age, and ethnicity, along with SLC22A3 and SLC22A4, influenced AUC. The maximum concentration was affected by age and SLC22A1, but after adjusting for dW, it was affected by sex, age, ethnicity, ABCG2, and SLC22A4. The time to reach the maximum concentration was influenced by sex, like half-life, which was also affected by SLC22A3. The volume of distribution and clearance was affected by sex, age, ethnicity and SLC22A3. Alternatively, the pharmacokinetics of metformin was unaffected by polymorphisms in ABCB1, SLC2A2, SLC22A2, or SLC47A1. Therefore, our study demonstrates that a multifactorial approach to all patient characteristics is necessary for better individualization.

Research Progress of Population Pharmacokinetic of Metformin.

Metformin is commonly used as first-line treatment for T2DM (type2 diabetes mellitus). Owing to the high pharmacokinetic (PK) variability, several population pharmacokinetic (PPK) models have been developed for metformin to explore potential covariates that affect its pharmacokinetic variation. This comprehensive review summarized the published PPK studies of metformin, aimed to summarize PPK models of metformin. Most studies described metformin pharmacokinetics as a 2-compartment (2-CMT) model with 4 study describing its pharmacokinetics as 1-compartment (1-CMT). Studies on metformin PPK have shown that obesity, creatinine clearance (CLCr), gene polymorphism, degree of renal function damage, and pathological conditions all have a certain impact on the PK parameters of metformin. It is particularly important to formulate individualized dosing regimens. For future PPK studies of metformin, we believe that more attention should be paid to special populations.

LC-MS/MS method for simultaneous determination of rivaroxaban and metformin in rat plasma: application to pharmacokinetic interaction study.

Aim: A reliable, sensitive and simple LC-MS/MS method has been established and validated for the quantitation of rivaroxaban (RIV) and metformin (MET) in rat plasma. Results: The procedure of method validation was conducted according to the guiding principles of EMA and US FDA. At the same time, the method was applied to pharmacokinetic interactions study between RIV and MET for the first time. When RIV and MET coadministered to rats, pharmacokinetic parameters of MET like AUC(0-t), AUC(0-∞) and Cmax had statistically significant increased. tmax of RIV was prolonged without affecting t1/2 obviously and Cmax was inhibited significantly (p < 0.05) by comparison to the single group. Conclusion: The results indicated that drug-drug interactions occurred when the coadministration of RIV and MET.

The mechanism of drug interactions of a selected antiarrhythmic drug with metformin, in different animal models

This study was carried out to understand the influence of a selected antiarrhythmic drug on the pharmacodynamics and pharmacokinetics of an antidiabetic drug in animal models. Pharmacodynamic and pharmacokinetic responses were determined by measurements of blood glucose and serum insulin and serum metformin to drug interactions between disopyramide and metformin. Single dose and multi dose studies showed that the maximum blood glucose reductions in normal and diabetic rats were at the 6th hour, and in rabbits at the 3rd hour. Glucose-insulin homeostasis was evaluated to assess the safety and effectiveness of the combination. There was a marginal increase in the pharmacokinetic parameters of metformin with multiple dose treatments of disopyramide but no significant changes in kinetic parameters between single and multiple dose studies, compared to metformine alone. There may be a possibility of disopyramide and metformin interaction at the excretion stage, or an additive pharmacodynamic action. This study validates the drug interaction in two dissimilar species, which indicates more probability of its occurrence in humans.

Investigation of possible pharmacokinetic interaction of metformin with sugar replacement sweeteners in rats

Metformin is widely used for type II diabetes. Sugar replacement sweeteners such as Aspartame and Stevia, are usually consumed concomitantly with other antidiabetics by patients The aim of this work is to investigate possible effects of two types of sweeteners; stevia and aspartame on the pharmacokinetic parameters of metformin in rats. A simple, validated bio-analytical HPLC method was developed to measure metformin in rat plasma. Three groups of rats, each of eight were subjected to this study. The first group was given metformin solution 20mg/kg alone , the second group was given 20 mg/kg metformin with 4mg/kg stevia and the third group was given 20 mg/kg metformin with 10 mg/kg aspartame on fasting state. Blood samples were taken on scheduled time interval up to 6 hours and analyzed for metformin concentration. Pharmacokinetic parameters were calculated by Non-Compartmental Model and data were interpreted. The results showed that administration of these two sweeteners did not have high effect on pharmacokinetics of metformin.

SLC47A1 gene rs2289669 G > A variants enhance the glucose-lowering effect of metformin via delaying its excretion in Chinese type 2 diabetes patients

AimsThe SLC47A1 gene encodes the multi-drug and toxic excretion-1(MATE1) protein, which plays a key role in the transport and excretion of metformin. This study is to clarify the influence of variants in SLC47A1 (rs2289669 G→A) on metformin pharmacokinetics and the long-term glucose-lowering effect of metformin. MethodsA total of 220 newly diagnosed type 2 diabetes patients were recruited, genotyped and divided into three groups by SLC47A1 genotypes (G/G, G/A, A/A). Ten patients in each group were randomly selected for metformin pharmacokinetics. All the participants received metformin oral treatment and were followed for one year. ResultsAfter one-year follow-up, the decline of HbA1c level was significantly greater in subjects with variant genotype (AA) than other two groups (−2.32% [−25.4mmol/mol] in AA vs. −1.16% [−12.7mmol/mol] in GA, −1.07% [−11.7mmol/mol] in GG, P<0.05). Then taking GG genotype as the referent, the association between AA genotype and change of HbA1c still existed after adjusted for age, sex, BMI, baseline HbA1c and diabetes duration (P<0.05). Pharmacokinetic parameters of metformin indicated that patients carrying MATE1 homozygous A had higher area under the plasma concentration versus time curve (AUC12h), but lower renal clearance (CLR) and renal clearance by secretion (CLSR) than other patients (all P<0.01). Multivariate lineal stepwise analysis further revealed that SLC47A1 genotype was an independent impact factor for urine excretion of metformin (P<0.01). ConclusionsSLC47A1 rs2289669 G>A variants improve the glucose-lowering effect of metformin through slowing its excretion in type 2 diabetes populations.

Effects of cysteine on metformin pharmacokinetics in rats with protein-calorie malnutrition: partial restoration of some parameters to control levels

Metformin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP)2C11, CYP2D1 and CYP3A1/2 in rats. The expression and mRNA levels of hepatic CYP2C11 and CYP3A1/2 are decreased in rats with protein-calorie malnutrition (PCM), but these levels are fully or partially restored to control levels in PMC rats by oral cysteine supplementation (PCMC rats). Thus, it would be expected that the pharmacokinetic parameters of metformin in PCM rats would be returned to control levels in PCMC rats. Metformin was administered i.v. (100 mg kg(-1)) and orally (100 mg kg(-1)) to control, CC (control rats with oral cysteine supplementation), PCM and PCMC rats. The following pharmacokinetic parameters of metformin following i.v. administration were restored from levels in PCM rats to levels in control rats in PCMC rats: intrinsic clearance (0.0350, 0.0309, 0.0253 and 0.0316 mL min(-1) mg(-1) protein for control, CC, PCM, and PCMC rats, respectively), total area under the plasma concentration-time curve from time zero to time infinity (AUC; 4110, 4290, 5540 and 4430 microg min mL(-1), respectively), and time-averaged non-renal clearance (8.12, 7.95, 5.94 and 8.17 mL min(-1) kg(-1), respectively). AUC values following oral administration were comparable between control and PCMC rats (1520, 1480, 2290 and 1680 microg min mL(-1), respectively).

Effects of bacterial lipopolysaccharide on the pharmacokinetics of metformin in rats

It was reported that the hepatic microsomal cytochrome P450 (CYP) 2C11, 2D1, and 3A1 (not via the CYP1A2, 2B1/2, and 2E1) were involved in the metabolism of metformin in rats. It was also reported that the expressions of CYP2C11 and 3A2 decreased in rats pretreated with Klebsiella pneumoniae lipopolysaccharide (KPLPS). Therefore, the pharmacokinetic parameters of metformin could be changed in rats pretreated with KPLPS. Hence, the pharmacokinetic parameters of metformin were compared after both intravenous and oral administration of the drug at a dose of 100 mg/kg to control rats and rats pretreated with KPLPS. After intravenous administration of metformin to rats pretreated with KPLPS, the total area under the plasma concentration–time curve from time 0 to ∞ (AUC) of the drug was significantly greater (40.5% increase) than the controls due to significantly smaller CL value (27.7% decrease) than the controls. The significantly smaller CL value could be due to significantly smaller both the CL R and CL NR values (34.0% and 18.1% decrease, respectively) than the controls. The significantly smaller CL NR value could be due to decrease in the expressions of CYP2C11 and 3A2 in rats pretreated with KPLPS. After oral administration of metformin, the AUC of the drug was not significantly different between two groups of rats, and this may be at least partly due to decrease in absorption from the gastrointestinal tract compared with the controls.

Dose-Independent Pharmacokinetics of Metformin in Rats: Hepatic and Gastrointestinal First-Pass Effects

Pharmacokinetic parameters of metformin were evaluated after intravenous and oral administration (50, 100, and 200 mg/kg) in rats. The hepatic, gastric, and intestinal first-pass effects were also measured after intravenous, intraportal, intragastric, and intraduodenal administration (100 mg/kg) in rats. The total area under the plasma concentration–time curve from time zero to time infinity (AUC) values were dose-proportional after both intravenous and oral dose ranges studied. After oral administration (100 mg/kg), approximately 4.39% of oral dose was not absorbed and extent of absolute oral bioavailability (F) value was approximately 29.9%. The gastrointestinal first-pass effect of metformin was approximately 53.8% of oral dose in rats (the gastric and intestinal first-pass effects were approximately 23.1 and 30.7%, respectively), and the hepatic first-pass effect was approximately 27.1% after absorption into the portal vein. Since approximately 41.8% of oral metformin was absorbed into the portal vein, the value of 27.1% is equivalent to 11.3% of oral dose. The first-pass effects of metformin in the lung and heart were almost negligible in rats. The low F value of metformin in rats was mainly due to considerable gastrointestinal first-pass effects. The stability of metformin, distribution of metformin between plasma and blood cells, and factors affecting protein binding of metformin to 4% human serum albumin were also discussed.

The effect of the ingestion of Ginkgo biloba extract (EGb 761) on the pharmacokinetics of metformin in non-diabetic and type 2 diabetic subjects—A double blind placebo-controlled, crossover study

Ginkgo biloba extract (EGb 761) has been shown to ameliorate some defects associated with the insulin resistance syndrome and so patients with Type 2 diabetes mellitus (T2DM) may be inclined to co-ingest the herb with their medications, such as metformin. This study was designed to determine if the co-ingestion of EGb 761 and metformin would alter the pharmacokinetic properties of metformin in T2DM patients and persons without diabetes, who may ingest it for other purposes. Normal glucose tolerance (NGT) subjects (n=10; age, 39.2+/-14.0 years; fasting plasma glucose (FPG), 90+/-7 mg/dl; body mass index (BMI), 24.1+/-3.7 kg/m(2)) and 10 T2DM patients (n=10; age, 51.7+/-8.9 years; FPG, 150+/-7 mg/dl; BMI, 33.7+/-5.7 kg/m(2)) completed a randomized, double-blind, placebo-controlled crossover study. They ingested either EGb 761 (12 0mg/day as a single dose) or a vegetable-based placebo during each arm for 3 months. At the end of each arm, the NGT subject ingested a single 500 mg dose of metformin (non-diabetics) and the T2DM subject took his/her prescribed metformin dose (250-850 mg) with 120 mg EGb 761. Blood and urine samples were collected over an 8-h period, and in the case of T2DM subjects, additionally over the first 2h of the subsequent 3 days. Ingestion of EGb 761 produced no significant changes in diagnostic laboratory tests in either group, except reducing glycosylated hemoglobin A(1c) levels (from 7.7+/-1.2 to 7.2+/-0.9%, P<0.05) in T2DM the subjects. The pharmacokinetic parameters of metformin were all significantly different (P<0.05) between the NGT (500 mg) and 8 out of 10 of the T2DM subjects who were prescribed 500 mg of metformin during the placebo cycles. During the EGb 761 cycles, only the elimination half-life in the T2DM subjects was significantly increased (0.117+/-0.085 to 0.141+/-0.100, P<0.05). The co-ingestion of 120 mg of EGb 761 and 500 mg of metformin did not significantly affect the pharmacokinetic properties of metformin. Further studies are required to verify this observation for smaller and larger dose of metformin with other doses of EGb 761, since T2DM patients on medication constitute a very heterogeneous group.

Biowaiver extension potential to BCS class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet

The biopharmaceutics classification system (BCS) allows biowaiver for rapid dissolving immediate-release (IR) products of Class I drugs (high solubility and high permeability). The possibility of extending biowaivers to Class III high solubility and low permeability drugs is currently under scrutiny. In vivo bioequivalence data of different formulations of Class III drugs would support such an extension. The objective of this work was to demonstrate the bioequivalence of two marketed IR tablet products of a Class III drug, metformin hydrochloride, that are rapidly dissolving and have similar in vitro dissolution profiles. The effect of race on the systemic exposure of metformin was also explored. A randomized, open-label, two-period crossover study was conducted in 12 healthy Chinese male volunteers. Each subject received a single-dose of 500 mg of each product after an overnight fasting. The plasma concentrations of metformin were followed for 24 h. No significant formulation effect was found for the bioequivalence metrics: areas under concentration–time curve (AUC0–t, AUC0–∞) and maximal concentration (Cmax). The 90% confidence intervals for the ratio of means were found within the acceptance range of 80–125% for the log-transformed data. Based on these results, it was concluded that the two IR products are bioequivalent. The pharmacokinetic parameters of metformin in Chinese for both products were similar and were in good agreement with those reported for metformin IR tablets in other ethnic populations. This study serves as an example for supporting biowaiver for BCS Class III drugs.