Imlunestrant is a next-generation, oral, selective estrogen receptor degrader approved for treating adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated advanced/metastatic breast cancer. Imlunestrant is metabolized partly by cytochrome P450 (CYP)3A4 oxidation and conjugation with glucuronic acid and sulfate; thus, pharmacokinetic and drug-drug interaction (DDI) studies for treatments utilizing similar pathways are essential for clinical development. Three open-label, phase 1 studies enrolled 182 healthy females of nonchildbearing potential to assess the tolerability, safety, and pharmacokinetics of imlunestrant as monotherapy or coadministered with other drugs. Drug concentrations were quantified by validated liquid chromatography-mass spectrometry. Participants tolerated imlunestrant at 200-800-mg doses, alone or with a CYP3A inhibitor (itraconazole), CYP3A inducer (carbamazepine), P-glycoprotein (P-gp) inhibitor (quinidine), and substrates of CYP2C8 (repaglinide), CYP2C19 (omeprazole), CYP2D6 (dextromethorphan), CYP3A (midazolam), P-gp (digoxin), and BCRP (rosuvastatin). Frequent treatment-related adverse events included headache (range, 4%-20%), diarrhea (2%-20%), and constipation (0%-16%). In the presence of imlunestrant, exposures (AUC0-∞) increased for dextromethorphan 1.33-fold (90% CI, 1.22-1.46), digoxin 1.39-fold (1.22-1.59), and rosuvastatin 1.49-fold (1.14-1.97). Imlunestrant exposure (AUC0-∞) decreased in combination with quinidine (CYP2D6 inhibitor) 0.87-fold (90% CI, 0.76-1.00) and carbamazepine (CYP3A4 inducer) 0.58-fold (0.49-0.69), but increased in combination with itraconazole (CYP3A4 inhibitor) 2.11-fold (1.77-2.53). Imlunestrant had no DDIs with CYP2C8 (repaglinide), CYP2C19 (omeprazole), and CYP3A4 (midazolam) substrates, or a P-gp inhibitor (quinidine), but weakly inhibited dextromethorphan (CYP2D6 substrate), digoxin (P-gp substrate), and rosuvastatin (BCRP substrate) clearance. Thus, considerations should be taken when imlunestrant is coadministered with strong CYP3A4 inhibitors, strong CYP3A4 inducers, and CYP2D6 and P-gp substrates where small changes in exposure may lead to toxicities.

This study investigated the potential drug-drug interaction (DDI) between eugenol (EUG) and repaglinide (RPG) in type 2 diabetes mellitus (T2DM). A T2DM rat model was established using a high-fat diet and streptozotocin (STZ). The single-dose group received 0.4 mg/kg RPG, and co-administration groups were pre-treated with EUG (50, 100, 150 mg/kg) for seven days before receiving a single dose of RPG (0.4 mg/kg). The blood glucose and pharmacokinetic parameters of RPG were assessed in the plasma samples of rats. The effect of EUG on RPG metabolic stability and cytochrome P3A (CYP3A) activity was evaluated in rat liver microsomes (RLM). In T2DM rats, RPG treatment showed a hypoglycemic effect, which was further promoted by EUG co-administration in a dose-dependent manner (p < 0.001). EUG co-administration affected the pharmacokinetics of RPG by increasing the area under the curve (AUC, increased 88.64%, 164.59%, and 244.72% vs single RPG, p < 0.001), plasma maximum concentration (Cmax, increased 18.61%, 53.58%, and 77.63% vs single RPG, p < 0.01), maximum concentration (Tmax, 1.0 h for EUG co-administration vs 0.5 h for single RPG), half-life (t1/2, prolonged 33.86%, 49.61%, and 88.19% vs single RPG, p < 0.01), mean retention time (MRT, prolonged 17.62%, 26.42%, 44.04% vs single RPG, p < 0.001), and decreased the clearance rate (Clz/F, decreased 48.92%, 63.31%, and 74.10% vs single RPG, p < 0.001) in a dose-dependent manner. In vitro RLM study, EUG improved the metabolic stability of RPG by prolonging the half-life (44.09 ± 3.25 min) and reducing the intrinsic clearance (30.55 ± 3.69 µL/min/mg protein). EUG also inhibited the activity of CYP3A with an IC50 of 7.90 ± 1.79 µM. Co-administration of EUG promoted the hypoglycemic effect of RPG through enhancing RPG systemic exposure in T2DM rats, potentially by improving RPG metabolic stability and inhibiting CYP3A activity.

A simple, rapid, precise, and selective first derivative spectrofluorimetric ([1]D) technique was suggested for repaglinide (REP) and febuxostat (FEB) simultaneous quantitation in pure, spiked human plasma samples and dosage forms. The approach was based on the first derivative transformation of the conventional fluorescence emission spectra. Excitation was fixed at 250 nm, and the first derivative of the emission spectra was recorded for each sample. Repaglinide (REP) was measured at 336.5 nm and febuxostat (FEB) at 363.5 nm in presence of each other using 0.2-M acetate buffer pH 3.9. Several experimental factors were examined and adjusted based on their effect on the fluorescence intensity. The validation was performed in accordance with ICH guidelines and the amplitude first derivative ([1]D) versus concentrations curves covered concentration ranges of 0.01-0.18 μg/mL for REP and 0.03-0.2 μg/mL for FEB. The quantification limits (LOQs) were 0.007 and 0.026 μg/mL for (REP) and (FEB), whereas lower detection limits (LODs) were 0.002 and 0.009 μg/mL, respectively. The suggested approach was effectively used to determine the two drugs in spiked human plasma samples in ranges 0.01-0.2 μg/mL for REP and 0.05-0.2 μg/mL for FEB. The proposed technique was effectively used to identify the (REP) and (FEB) in multiple pharmaceutical products.

Cytochrome P450 2C8 (CYP2C8) is known to cause drug interactions via pharmacokinetic alterations of drugs, but it's also explicitly crucial for endogenous metabolism, like the generation of epoxyeicosatrienoic acids (EETs) from arachidonic acid. CYP2C8 expression is reported to be altered in various cancers, where CYP2C8-mediated EETs promote tumorigenesis. Conversely, thymoquinone, an extensively used complementary medicine, has emerged as a promising candidate against cancer due to its ability to curb tumorigenesis. Nevertheless, to date, limited information is available about the impact of thymoquinone on CYP2C8 inhibition. Therefore, we planned to explore the same using in silico, in vitro, and in vivo approaches. The current results reveal the followings: (a) thymoquinone could markedly inhibit CYP2C8 based on study using amodiaquine N-deethylation in human liver microsomes (HLM); (b) thymoquinone could strongly interact with the active site of the human CYP2C8 as demonstrated by molecular docking analysis; (c) thymoquinone could restrict the metabolic depletion of repaglinide (a CYP2C8 substrate) in rat liver microsomes; (d) thymoquinone altered the pharmacokinetic profile of repaglinide (a CYP2C8 substrate) in rats, resulting in repaglinide's increased systemic exposure and reduced clearance; (e) thymoquinone could retard EET's formation in HLM. Further studies are warranted to evaluate the biological significance of thymoquinone-mediated modulation of the CYP2C8/EET axis in relevant cancer models.

Background/Objectives: Cyclodextrin-based ternary systems are widely used to improve the solubility of poorly soluble drugs. Amino acids such as L-arginine may further increase dissolved drug concentrations and reduce precipitation under physiologically relevant conditions. In many systems, apparent solubility enhancement is influenced simultaneously by drug ionization, inclusion complex formation, multicomponent interactions, and solid-liquid equilibria. This study presents a physicochemical modeling approach for analyzing pH-dependent solubility enhancement and precipitation behavior in drug-cyclodextrin-L-arginine systems. Methods: The model combines acid-base equilibria, binary inclusion complexation, ternary association, and explicit solid-phase partitioning within a unified mass-balance treatment. The approach was applied to representative ternary systems containing repaglinide, sulfadiazine, cefixime, and meloxicam. Results: Quantitative comparison with published phase-solubility data for the repaglinide-HPβCD-L-arginine system confirmed the numerical consistency of the model. The calculated profiles showed that enhanced solubilization and reduced precipitation occur only within specific pH regions determined by coupled equilibrium effects. For cefixime and meloxicam, the calculations were interpreted as predictive applications because directly comparable validation datasets were not available. Outside the favorable pH regions, a substantial fraction of the drug remained in the solid phase. Conclusions: These observations support the importance of pH and multicomponent interactions in controlling formulation performance in cyclodextrin-containing systems. The obtained profiles may support preliminary optimization of formulation pH and excipient composition before experimental screening.

Reversible biomolecular interactions play a vital role in numerous biological processes. One of the techniques that has been developed to evaluate solution-phase binding and rate constants for such processes is ultrafast affinity extraction (UAE). In UAE, a microcolumn containing an immobilized capture agent is used to quickly remove the free form of a target solute from a sample that also contains a soluble binding agent. This separation is typically done on the millisecond-to-second time scale. The measured level of the captured fraction can then be utilized to estimate the binding and rate constants for the interactions between the solute and binding agent in the sample. Covalent coupling methods have been used in the past with UAE to immobilize serum proteins as capture agents for various drugs. This work examines the combination of non-covalent entrapment to immobilize human serum albumin (HSA) as a capture agent within microcolumns that are then used in UAE to study drug interactions with soluble HSA. This combined approach is evaluated using racemic warfarin and repaglinide as model drugs with known single-site or multi-site binding to this protein. The theoretical and experimental behavior of UAE is examined in each case. The binding and rate constants determined by this method are also compared to reference values, including results obtained by UAE using a covalently immobilized capture agent. The results are then used to identify the potential strengths or limitations of this approach and to provide guidelines on how this method can be applied in the future to examine other types of biointeractions.

This study investigated genetic determinants of the pharmacokinetics of the CYP2C8 index drugs repaglinide and gemfibrozil, and their interaction in healthy participants. Sequencing data from a study with montelukast revealed a novel functional CYP2C8 allele (rs2071426, CYP2C8*19), predicted to create an intronic splice donor site. In human liver samples, CYP2C8*19 associated with transcript-specific changes in CYP2C8 mRNA expression, reduced CYP2C8 protein expression, and decreased enzyme activity. Consistently, participants with the CYP2C8*19/*19 genotype had 45% greater area under the plasma repaglinide concentration-time curve from time zero to infinity (AUC0-∞) than participants with CYP2C8*1/*1 (P = 1.6 × 10[-4]). Participants with CYP2C8*1/*3 had 26% smaller AUC0-∞ (P = 0.0033) and those with CYP2C8*1/*4 had 51% greater AUC0-∞ (P = 8.2 × 10[-4]). The fold increase in repaglinide AUC0-∞ caused by gemfibrozil was 36% (P = 1.3 × 10[-4]) smaller in CYP2C8*19/*19 participants than in CYP2C8*1/*1 participants. In a genome-wide association study (GWAS), SLCO1B1 c.521 T>C (rs4149056) associated with increased repaglinide AUC0-∞ (P = 4.5 × 10[-15]; n = 172) and SLCO1A2 variants associated with decreased AUC0-∞ (P < 10[-8]). In a GWAS of repaglinide after gemfibrozil pretreatment, SLCO1C1 variants associated with decreased AUC0-∞ (P < 1.6 × 10[-8]; n = 66). Participants with the poor function SLCO1B1 genotype showed a 32% smaller fold increase in repaglinide AUC0-∞ following gemfibrozil than participants with the normal function SLCO1B1 genotype (P = 0.0045). This study characterizes CYP2C8*19 as a novel decreased function allele and shows that CYP2C8 and SLCO1B1 genotypes affect the gemfibrozil-repaglinide interaction.

Diabetes mellitus (DM) represents a major and growing global health challenge. Among antidiabetic medications, sulfonylureas and meglitinides remain clinically relevant insulin secretagogues for the management of type 2 DM (T2DM). However, many drugs in these classes belong to Biopharmaceutics Classification System (BCS) Class II, which are characterized by low aqueous solubility and high membrane permeability. These physicochemical constraints result in slow dissolution, variable oral absorption, suboptimal bioavailability and inadequate glycemic control. Converting drugs into their amorphous form can enhance solubility and dissolution; however, amorphous drugs are inherently unstable and prone to recrystallization, limiting their practical use. Amorphous solid dispersion (ASD), which incorporates poorly soluble antidiabetic drugs into a polymeric matrix, offers a promising strategy to overcome these limitations. The polymeric carrier stabilizes the drug in its high-energy amorphous state, improving solubility, dissolution, and ultimately, bioavailability. In ASD systems, drug molecules are dispersed within the polymer matrix at the molecular level, forming extremely fine dispersion domains that may be even smaller than conventional nanoparticle systems, thereby enhancing apparent solubility and dissolution. This review provides a comprehensive overview of ASD applications in antidiabetic therapy, discussing the principles of ASD, commonly used polymeric carriers, fabrication methods, and recent in vitro and in vivo findings. Studies consistently show that ASD formulations of antidiabetic drugs such as glimepiride, repaglinide, gliclazide, gliquidone, and glyburide enhance insulin secretion and contribute to more effective glycemic control, showing the potential of ASD in improving the therapeutic performance of poorly soluble antidiabetic agents. By enhancing solubility, stability, and bioavailability, ASD technology holds significant promise for developing more potent and effective antidiabetic therapies, ultimately supporting better patient care and addressing the global burden of diabetes mellitus.

For prehospital providers, there are several causes for the patient with altered mental status or being unconscious to include the mnemonic AEIOU TIPS for Alcohol and acidosis, Endocrine, Epilepsy, Electrolytes, Encephalopathy, Infection, Opiates, Overdose, Uremia, Underdose, Trauma (head injury and blood loss), Insulin, Poisoning, Psychosis, Stroke, Seizure, and Syncope. Hypoglycemia, or low blood glucose level, is one of the most common causes of altered mental status for patients with and without diabetes. Estimates are that 1 to 2 percent of prehospital encounters and 7% of refusals are for hypoglycemia.[1][2] Diabetes mellitus often referred to as "diabetes" or "sugar" by laypeople is the most common endocrine disorder where the body does not either produce enough insulin or has a resistance to the circulating insulin, and is characterized by high blood sugar levels over prolonged periods. The three main types of diabetes are type I (previously referred to as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset), type II (formerly referred to as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset) and gestational.[3] Insulin is an anabolic hormone produced in the beta cells of the pancreatic islets. The primary function of insulin is to regulate the metabolism of carbohydrates, protein, and fat through the absorption of glucose sugar from the blood into the liver, fat, and skeletal muscle cells. These small glucose molecules are then converted into larger molecules and stored for later usage.  Type 1 Diabetes Mellitus (T1DM) [4] This condition is commonly referred to as insulin-dependent diabetes or previously as childhood/adolescent-onset diabetes. It accounts for approximately 5% to 10% of all cases of diabetes. It can be related to the autoimmune destruction of insulin-producing beta cells in the islets of the pancreas from different causes, including genetic susceptivity, viral illness, toxins or alcohol-induced pancreatitis, or some dietary factors.  The age group affected is usually children and adolescents, but adults can develop T1DM.  As the name "insulin-dependent" implies, it requires the administration of subcutaneous insulin via intermittent injections or pump infusion. Type 2 Diabetes Mellitus (T2DM) [4] [5] This variant is commonly referred to as non-insulin diabetes or previously as adult-onset diabetes.  It accounts for approximately 90% of all cases of diabetes.  It is related to the desensitization of insulin/insulin resistance (response to insulin becomes diminished) in various tissues. Initially, there is an increase in insulin production, but this decreases over time. T2DM most commonly presents in persons older than 45 years, but it increasingly occurs in children, adolescents, and younger adults due to rising levels of obesity, physical inactivity, and energy-dense diets. Gestational Diabetes Mellitus (GDM) Hyperglycemia first detected during pregnancy is classified as gestational diabetes mellitus (GDM). Although it can occur anytime during pregnancy, GDM generally affects pregnant women during the second and third trimesters. According to the American Diabetes Association (ADA), GDM complicates 7% of all pregnancies. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future.  Types of Therapies [6] Therapy for hyperglycemia is dependant upon how much insulin the body is producing, or how well that insulin that is produced is working.  The majority of patients with T2DM will be on an oral type of medication.  Patients with T1DM will be on a combination of either long-acting insulin with short-acting as a sliding scale, intermediate-acting insulin with short-acting insulin as a sliding scale, combination premixed insulin, or be on an insulin pump. Hypoglycemia  One of the public health concerns for diabetes mellitus and unintended complications for the reduction in blood glucose levels is hypoglycemia.[1][7][8] Hypoglycemia, by definition, is a plasma glucose concentration below 70 mg/dL, with most patients not having signs or symptoms until the plasma glucose concentrations drop below 55 mg/dL.[9]  Low plasma glucose concentration that requires assistance from another individual qualifies as severe hypoglycemia, and by context, all EMS encounters fall into this category.[1][10]  There has been an increase in morbidity (poor quality of life, series falls or car accidents, dementia, and hospitalization) and mortality related to severe hypoglycemia.[1]  Based upon 2015 data from NEMSIS, prehospital activation for diabetes-related cases accounts for about 2.3% of all activations, with the primary EMS encounter being hypoglycemia.[11] Patients experiencing severe hypoglycemia or other diabetes-related concerns typically reach out for help by calling 911 who may dispatch a fire department or EMS agency depending on the jurisdiction. Care is then provided by the first on scene provider who may be an emergency medical technician (EMT) intermediate or advanced emergency medical technician (IEMT or AEMT) or paramedic. Treat and release versus transport of patients with hypoglycemia by EMS providers depends on the clinical guidelines or protocols from either the state or regional level by medical directors. It is important to understand that patients with severe hypoglycemia are at a higher risk of having complications related to the hypoglycemic state.  Villani et al. indicated that approximately 50% of patients with severe hypoglycemia required transport to the hospital, and of that group, 41.3% were admitted to the hospital.[12][13][14]  One of the first studies on the topic of treating and releasing hypoglycemic patients in the field was "Development and Evaluation of Criteria Allowing Paramedics to Treat and Release Patients Presenting with Hypoglycemia: A Retrospective Study" published in Prehospital and Disaster Medicine in 1991.   Their study design proposed five criteria that would allow for appropriate release that would not require additional treatment from prehospital providers to include: 1. The patient has a history of type 1 or type 2 diabetes. 2. Blood sugar prior to treatment is below 4.4 mmol/L or 80 mg/dL. 3. Blood sugar after treatment is equal to or greater than 4.4 mmol/L or 80 mg/dL. 4. The patient has a normal mental status within 10 minutes of treatment.  5. The patient does not have any other complicating factors that required ED evaluation to such alcohol, chest pain, dyspnea, injuries related to falls, and/or renal dialysis. A 2016 study by Rostykus et al. reviewed prehospital clinical guidelines for hypoglycemia in 185 EMS agencies in the United States.  It revealed that less than half allowed for non-transport of patients with hypoglycemia after the low plasma glucose level was corrected.[15] A study by Moffet et al. looked at hypoglycemic patients treated by EMS in Alameda County from 2013 to 2015 and found that the transport rate was 13.5%. The demographic trends for those non-transported patients were adult patients < 60 years of age, males, finger stick blood glucose levels > 60 mg/dl, and EMS arrival times between 1800 and 0600.[1]

Repaglinide (RPG) is a commonly prescribed oral antihyperglycemic agent for the control of postprandial hyperglycemia. However, the safety profile of RPG regarding cardiac tissues has not been explored yet. The present study examined the cardiotoxic effects of RPG in male Sprague Dawley rats at different doses using integrated molecular, biochemical, functional and histopathological approaches. Thirty-two rats were randomly allocated to four groups (n = 8), that is, control and RPG-treated (0.7, 1.4, and 4 mg/kg/day) groups for 4 weeks. RPG administration significantly upregulated hypoxia-angiogenic markers (HIF-1α, VEGF-A, VEGFR-2, and EPO) and downregulated ANGPT1, which is suggestive of disrupted vascular stabilization. A strong inflammatory response was noticed with marked activation of TLR4/MyD88/NF-κB signaling and increased COX-2, IL-6, IL-1β, and TNF-α expression. Oxidative stress was markedly increased at a dose-dependent manner, as shown by degradation in antioxidant enzyme (CAT, SOD, GSR, GPx, GST, and HO-1,) and high increments in MDA and ROS levels. Echocardiographic analysis showed a gradual low heart rate, ventricular dilation, thickening of the ventricular walls, and increasing of EDV and ESV, which is a sign of structural remodeling and impairment of the ventricle. Serum cardiac biomarkers (CK-MB, CPK, Troponin-I, Troponin-T, LDH, BNP, NT-proBNP, and CRP) were significantly elevated following the administration of RPG at varying concentrations. Apoptotic signaling was activated significantly as shown by the increased levels of Bax, Caspase-3, and Caspase-9 with reduced expression of Bcl-2 after RPG intoxication. Moreover, RPG exposure induced histopathological alterations including degenerative myocardial lesions, interstitial edema, inflammatory infiltration, and early fibrotic changes. Collectively, these results show that RPG causes profound cardiotoxicity in a dose-dependent manner, mediated by oxidative stress, inflammatory activation, hypoxia-angiogenic imbalance, apoptotic signaling, and structural remodeling. This study demonstrates the importance of thorough cardiovascular safety evaluation of antidiabetic therapies and calls for further translational evaluation to evaluate potential clinical implications.

No information is available on the use of repaglinide during breastfeeding. Repaglinide is a weak acid that is over 98% protein bound, so it is unlikely to pass into breastmilk in clinically important amounts. Monitor breastfed infants for signs of hypoglycemia such as jitteriness, excessive sleepiness, poor feeding, seizures cyanosis, apnea, or hypothermia. If there is concern, monitoring of the breastfed infant's blood glucose is advisable during maternal therapy with repaglinide.[1] However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.