Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

Download Full-text

Application of Statistical Tooling Techniques for Designing of Carvedilol Nanolipid Transferosomes and its Dermatopharmacokinetic and Pharmacodynamic Studies

Pharmaceutical Nanotechnology ◽

10.2174/2211738508666200928164820 ◽

2020 ◽

Vol 8 (6) ◽

pp. 452-470

Author(s):

Brito R. Selvaraj ◽

Seshaiah K. Sridhar ◽

Bhaskar R. Kesavan ◽

Sucharitha Palagati

Keyword(s):

Particle Size ◽

Plasma Concentration ◽

Dosage Form ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Entrapment Efficiency ◽

Transdermal Patch ◽

In Vitro Drug Release

Background: The hypothesis is to augment the bioavailability and therapeutic potential of low bioavailable Carvedilol (25-35%) through Nanostructured Lipid Carrier (NLC) loaded Transdermal patch (Nanolipid Transferosomes). Methods: Box-Behnken design was designed to formulate NLC through a hot homogenization technique. About 17 formulations (C1-C17) were formulated by varying the critical material attribute and critical process parameter. Optimization was done based on its critical quality attributes like particle size, zeta potential and entrapment efficiency. Selected NLC (C16) has been fabricated into a transdermal patch through solvent evaporation technique and estimated for thickness, weight variation, moisture content, folding endurance, drug content, in vitro drug release, ex vivo skin permeation studies 48 hrs, in vitro drug release kinetic studies and skin irritation studies. In vivo pharmacokinetics and pharmacodynamic study parameters were compared between carvedilol loaded NLC transdermal patch and a conventional formulation (Coreg CR). Results: NLC (C16) was selected as the best formulation based on desirable, less particle size (201.1 ± 2.02 nm), more zeta potential (-37.2 ± 1.84mV) and maximum entrapment efficiency (87.54 ± 1.84%). Experimental investigations of in vivo dermatopharmacokinetic data shown statistically significant changes (p<0.05) in the parameter (increased AUC0-α, MRT with decreased Cmax, Tmax) when administered through the transdermal patch and on compared to the conventional dosage form. It was observed that there was a significant change with p<0.05 among the pharmacokinetic factors of conventional Carvedilol formulation, Carvedilol NLC and Carvedilol NLC loaded Transdermal patch with a maximum time of peak plasma concentration (Tmax) of 4 hrs, 8 hrs and 8 hrs; maximum peak plasma concentration (Cmax) of 0.258 μg/ml, 0.208 μg/ml and 0.108 μg/ml. Area Under Curve (AUC0-α) was established to be 125.127 μg/ml/h, 132.576 μg/ml.h and 841.032 μg/ml.h. Mean Residence Time (MRT0- α) of the drug was established to be 17 hrs, 19 hrs and 82 hrs, respectively. This data reveals the impact of NLC on the enhancement of bioavailability through a transdermal patch. In vivo pharmacodynamic studies confirm that NLC loaded transdermal patch (Nanolipid Transferosomes) shows a significant control in blood pressure for 48 hrs when compared to the conventional dosage form. Conclusion: This research data concludes that NLC loaded transdermal patch (Nanolipid Transferosomes) was a suitable candidate to enhance the bioavailability of low bioavailable drug-like Carvedilol. Lay Summary: It was inferred from the literature that NLC filled transdermal patches were a novel strategy to increase the solubility and permeability of Carvedilol, which has less bioavailability. It reveals that there was no reproducible preparation for the NLC. It also reveals that the option of formulation and process parameters for the formation of NLC is not clearly justified. On account of this, an uniquely validated and optimized formulation technique was developed for NLC with low soluble and poorly bioavailable carvedilol, tested in Albino wistar rats for enhancement of bioavailability, the same study has been performed and proved.

Download Full-text

Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Pharmacology ◽

10.1159/000480090 ◽

2017 ◽

Vol 100 (5-6) ◽

pp. 301-307

Author(s):

Maria Bianca Abrudan ◽

Dana Maria Muntean ◽

Daniela Saveta Popa ◽

Ana-Maria Gheldiu ◽

Maria Adriana Neag ◽

...

Keyword(s):

Drug Interaction ◽

Plasma Concentration ◽

Metabolic Rate ◽

Liver Microsome ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Femoral Vein ◽

Plasma Concentrations ◽

Drug Drug Interaction

Background/Aims: The aim of this study was to investigate the drug-drug interaction between carvedilol and citalopram based on carvedilol metabolism in vitro and his pharmacokinetics (PKs) in vivo after the oral administration of the single drug and both drugs, and reveal citalopram effects on the PKs of carvedilol. Methods: Each rat was cannulated on the femoral vein, prior to being connected to BASi Culex ABC®. Carvedilol was orally administrated in rats (3.57 mg/kg body weight [b.w.]) in the absence of citalopram or after a pre-treatment with multiple oral doses of citalopram (1.42 mg/kg b.w.). Plasma concentrations of carvedilol were determined using high-performance liquid chromatography-MS at the designated time points after drug administration, and the main PK parameters were calculated by noncompartmental analysis. In addition, effects of citalopram on the metabolic rate of carvedilol were investigated using rat-pooled liver microsome incubation systems. Results: During co-administration, significant increases of the area under the plasma concentration-time curve as well as of the peak plasma concentration were observed. The rat-pooled liver microsome incubation experiment indicated that citalopram could decrease the metabolic rate of carvedilol. Conclusion: Citalopram co-administration led to a significant alteration of carvedilol's PK profile in rats; it also demonstrated, in vitro, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition.

Download Full-text

TO STUDY THE PHARMACOKINETIC HERB-DRUG INTERACTION OF MOMORDICA CHARANTIA FRUIT EXTRACT AND PURE CHARANTIN WITH NATEGLINIDE IN RATS

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2021v13i9.40967 ◽

2021 ◽

pp. 1-5

Author(s):

AISHWARYA R. BALAP

Keyword(s):

Drug Interaction ◽

Plasma Concentration ◽

Drug Interactions ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Systemic Exposure ◽

Momordica Charantia ◽

Exposure Level ◽

Fruit Extract

Objective: Momordica charantia fruit extract and antidiabetic drug Nateglinide might be used simultaneously in the treatment of diabetes, so the objective of this study was to investigate pharmacokinetic herb-drug interactions of Momordica charantia fruit extract and pure charantin with nateglinide in rats. Methods: After oral co-administration of Momordica charantia fruit extract (250 mg/kg) and Charantin (10 mg/kg) with nateglinide in rats, drug concentration parameters peak plasma concentration (Cmax), time to reach peak plasma concentration (tmax), elimination half-life (t1/2), apparent volume of distribution (Vd), plasma clearance (Cl), and area under the curve (AUC) were calculated by using the non-compartment model. Results: NAT was absorbed into the circulatory system and reached its peak concentration approximately 2 h after being administered individually. tmax of groups co-administered NAT+MCE has been changed to 4h. A significant decrease in Cmax of NAT from 16.28 µg/ml to 11.37 µg/ml and 10.37 µg/ml with NAT with charantin and NAT with MCE groups, respectively. AUC of NAT decreased from 84.53 h/µg/ml to 53.63 h/µg/ml and 47.17 h/µg/ml by co-administration with Charantin and MCE respectively. Co-administration of nateglinide with Charantin and Momordica charantia fruit extract decreased systemic exposure level of nateglinide in vivo with decreasing Cmax and AUC and an increase in t1/2, Cl and Vd. Conclusion: From this study, it can be concluded that nateglinide, Momordica charantia fruit extract, and pure Charantin existed pharmacokinetic herb-drug interactions in the rat which has to be correlated with the anti-diabetic study. Further studies should be done to understand the effect of other herbal ingredients of Momordica charantia fruit extract on nateglinide as well as to predict the herb-drug interaction in humans.

Download Full-text

Effect of quercetin on the transport of ritonavir to the central nervous system in vitro and in vivo

Acta Pharmaceutica ◽

10.1515/acph-2016-0009 ◽

2016 ◽

Vol 66 (1) ◽

pp. 97-107 ◽

Cited By ~ 3

Author(s):

Gongwen Liang ◽

Na Li ◽

Liping Ma ◽

Zhonglian Qian ◽

Yuwen Sun ◽

...

Keyword(s):

Plasma Concentration ◽

Tissue Distribution ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Phase 1 ◽

Control Group ◽

Intracellular Accumulation ◽

Sprague Dawley ◽

Time Curve

Abstract The aim of this study was to identify an effective flavonoid that could improve the intracellular accumulation of ritonavir in human brain-microvascular endothelial cells (HBMECs). An in vivo experiment on Sprague-Dawley rats was then designed to further determine the flavonoid’s impact on the pharmacokinetics and tissue distribution of ritonavir. In the accumulation assay, the intracellular leve l of ritonavir was increased in the presence of 25 mmol L−1 of flavonoids in HBMECs. Quercetin showed the strongest effect by improving the intracellular accumulation of ritonavir by 76.9 %. In the pharmacokinetic study, the presence of quercetin in the co-administration group and in the pretreatment group significantly decreased the area under the plasma concentration-time curve (AUC0–t) of ritonavir by 42.2 % (p < 0.05) and 53.5 % (p < 0.01), and decreased the peak plasma concentration (cmax) of ritonavir by 23.1 % (p < 0.05) and 45.8 % (p < 0.01), respectively, compared to the control group (ritonavir alone). In the tissue distribution study, the ritonavir concentration in the brain was significantly increased 2-fold (p < 0.01), during the absorption phase (1 h) and was still significantly higher (p < 0.05) during the distribution phase (6 h) in the presence of quercetin.

Download Full-text

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

Medicinal Chemistry ◽

10.2174/1573406416666201120102905 ◽

2020 ◽

Vol 16 ◽

Author(s):

Xi He ◽

Wenjun Hu ◽

Fanhua Meng ◽

Xingzhou Li

Keyword(s):

Plasma Concentration ◽

Broad Spectrum ◽

Plasma Concentrations ◽

Antiviral Drug ◽

Systemic Exposure ◽

Pharmacokinetic Profile ◽

Hydroxyl Group ◽

First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

Download Full-text

Developing a new formulation of sodium phenylbutyrate

Archives of Disease in Childhood ◽

10.1136/archdischild-2012-302398 ◽

2012 ◽

Vol 97 (12) ◽

pp. 1081-1085 ◽

Cited By ~ 25

Author(s):

Nathalie Guffon ◽

Yves Kibleur ◽

William Copalu ◽

C Tissen ◽

Joerg Breitkreutz

Keyword(s):

Plasma Concentration ◽

Healthy Adult ◽

Taste Perception ◽

In Vitro Dissolution ◽

Time Curve ◽

New Formulation ◽

Adult Volunteers ◽

Sodium Phenylbutyrate

BackgroundSodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control.ObjectivesA new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers.ResultsThe in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of ∼10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (Cmax) or for area under the plasma concentration–time curve (AUC). CI for Cmax and AUC0–inf of NaPB were included in the bioequivalence range of 0.80–1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements.ConclusionsIn vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD.

Download Full-text

Development of Level A In Vitro–Vivo Correlation for Electrosprayed Microspheres Containing Leuprolide: Physicochemical, Pharmacokinetic, and Pharmacodynamic Evaluation

Pharmaceutics ◽

10.3390/pharmaceutics12010036 ◽

2020 ◽

Vol 12 (1) ◽

pp. 36

Author(s):

Dong-Seok Lee ◽

Dong Wook Kang ◽

Go-Wun Choi ◽

Han-Gon Choi ◽

Hea-Young Cho

Keyword(s):

Plasma Concentration ◽

Prediction Error ◽

Subcutaneous Administration ◽

In Vitro Dissolution ◽

Burst Release ◽

Maximum Plasma ◽

Time Curve ◽

In Vivo Dissolution

This study optimized the preparation of electrosprayed microspheres containing leuprolide and developed an in vitro–in vivo correlation (IVIVC) model that enables mutual prediction between in vitro and in vivo dissolution. The pharmacokinetic (PK) and pharmacodynamic (PD) study of leuprolide was carried out in normal rats after subcutaneous administration of electrosprayed microspheres. The parameters of the IVIVC model were estimated by fitting the PK profile of Lucrin depot® to the release compartment of the IVIVC model, thus the in vivo dissolution was predicted from the in vitro dissolution. From this correlation, the PK profile of leuprolide was predicted from the results of in vivo dissolution. The IVIVC model was validated by estimating percent prediction error (%PE) values. Among prepared microspheres, an optimal formulation was selected using the IVIVC model. The maximum plasma concentration and the area under the plasma concentration–time curve from zero to infinity from the predicted PK profile were 4.01 ng/mL and 52.52 h·ng/mL, respectively, and from the observed PK profile were 4.14 ng/mL and 56.95 h·ng/mL, respectively. The percent prediction error values of all parameters did not exceed 15%, thus the IVIVC model satisfies the validation criteria of the Food and Drug Administration (FDA) guidance. The PK/PD evaluation suggests that the efficacy of OL5 is similar to Lucrin depot®, but the formulation was improved by reducing the initial burst release.

Download Full-text

Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis

Scientific Reports ◽

10.1038/s41598-019-53628-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Satoshi Nakano ◽

Shuhei Osaka ◽

Yusuke Sabu ◽

Kei Minowa ◽

Saeko Hirai ◽

...

Keyword(s):

Plasma Concentration ◽

Intrahepatic Cholestasis ◽

Clinical Symptoms ◽

Peak Plasma ◽

Oral Treatment ◽

Peak Plasma Concentration ◽

Open Label ◽

Time Curve ◽

Single Dose Study ◽

Progressive Familial Intrahepatic Cholestasis

AbstractProgressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved regimen for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0–3.0;P = 0.003) and 2.4-fold (95% CI, 1.7–3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.

Download Full-text

Interaction of Metoprolol, Propranolol and Atenolol with Cimetidine

Clinical Science ◽

10.1042/cs063451s ◽

1982 ◽

Vol 63 (s8) ◽

pp. 451s-453s ◽

Cited By ~ 3

Author(s):

W. Kirch ◽

H. Spahn ◽

H. Köhler ◽

E. Mutschler

Keyword(s):

Plasma Concentration ◽

Healthy Volunteers ◽

Peak Plasma ◽

Plasma Concentrations ◽

Concurrent Administration ◽

Time Curve ◽

Concentration Time ◽

Plasma Concentration Time Curve

1. Pharmacokinetics of metoprolol, propranolol and atenolol were investigated in six healthy volunteers after 7 days of oral monotherapy with these drugs and after 7 days concurrent administration, with each of these β-adrenoceptor antagonists with cimetidine. 2. Cimetidine did not interact with atenolol, whereas mean peak plasma concentrations of metoprolol were increased by 70%, and those of propranolol by 95% with concurrent administration of cimetidine (P < 0.05). 3. The area under the plasma concentration-time curve for propranolol and metoprolol was similarly increased (P < 0.05).

Download Full-text

OPTIMIZATION OF STATISTICALLY DESIGNED ACECLOFENAC FAST DISSOLVING TABLETS EMPLOYING STARCH GLUTAMATE AS A NOVEL SUPERDISINTEGRANT

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2020v12i1.34987 ◽

2019 ◽

pp. 77-88

Author(s):

R. SANTOSH KUMAR ◽

SAHITHI MUDILI

Keyword(s):

Drug Release ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

In Vitro Dissolution ◽

Pharmacokinetic Studies ◽

Disintegration Time ◽

Short Period ◽

Dissolution Efficiency

Objective: To optimize aceclofenac fast dissolving tablets employing starch glutamate as novel superdisintegrant by 23factorial design to improve bioavailability and enhance patient compliance. Methods: Starch glutamate was prepared by the esterification process. Starch glutamate physical and micromeritics properties had been evaluated and the prepared starch glutamate was used as a superdisintegrant for the formulation of the fast dissolving tablets of aceclofenac by direct compression method and optimized by employing 23factorial design. The prepared aceclofenac fast dissolving tablets were evaluated for post compression parameters as well as in vitro and in vivo release characteristics. Optimized formulation stability studies were performed at accelerated conditions for 6 mo as per ICH and WHO guidelines. Results: The prepared starch glutamate was amorphous, insoluble in aqueous and organic solvents were tested. Fast dissolving tablets of aceclofenac were formulated by employing starch glutamate as a superdisintegrant showed good tablet properties and showed an increased dissolution efficiency of the drug. Among all the formulations (F1 to F8), the formulation F8 containing 5% concentration of starch glutamate, croscarmellose sodium and, crospovidone as a superdisintegrants showed 99.7±0.15% of drug release within 5 min. Whereas the formulation F2 containing 5% concentration of starch glutamate, drug release characters were comparable to the formulation F8. Optimized formulation F2 attained peak plasma concentration within a short period and showed increased relative bioavailability of the drug. Conclusion: From the physical properties, disintegration time, in vitro dissolution studies and pharmacokinetic studies, it was concluded that fast dissolving tablets of aceclofenac tablets formulated by employing starch glutamate as a superdisintegrant enhanced the dissolution efficiency and improved the bioavailability of the drug as compared to the pure drug and stable.

Download Full-text