scholarly journals Herb-Drug Interaction ofPaullinia cupana(Guarana) Seed Extract on the Pharmacokinetics of Amiodarone in Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Márcio Rodrigues ◽  
Gilberto Alves ◽  
Nulita Lourenço ◽  
Amílcar Falcão
Keyword(s):  
Drug Interaction ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Systemic Exposure ◽  
Therapeutic Index ◽  
Great Decrease ◽  
Tissue Concentrations ◽  
Paullinia Cupana ◽  
Narrow Therapeutic Index Drug ◽  
First Time

Paullinia cupanais used in weight-loss programs as a constituent of medicinal/dietary supplements. This study aimed to assess a potential herb-drug interaction among a standardized (certified)Paullinia cupanaextract and amiodarone (narrow therapeutic index drug) in rats. In a first pharmacokinetic study rats were simultaneously coadministered with a single dose ofPaullinia cupana(821 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.), and in a second study rats were pretreated during 14 days withPaullinia cupana(821 mg/kg/day, p.o.) receiving amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. Blood samples were collected at several time points after amiodarone dosing, and several tissues were harvested at the end of the experiments (24 h after dose). Plasma and tissue concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone) were measured and analysed. A significant reduction in the peak plasma concentration (73.2%) and in the extent of systemic exposure (57.8%) to amiodarone was found in rats simultaneously treated withPaullinia cupanaand amiodarone; a decrease in tissue concentrations was also observed. This paper reports for the first time an herb-drug interaction betweenPaullinia cupanaextract and amiodarone, which determined a great decrease on amiodarone bioavailability in rats.

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

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.

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

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 782
Author(s):  
Ji-Min Kim ◽  
Seong-Wook Seo ◽  
Dong-Gyun Han ◽  
Hwayoung Yun ◽  
In-Soo Yoon
Keyword(s):  
Plasma Concentration ◽  
Liver Microsome ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Systemic Exposure ◽  
Concurrent Administration ◽  
Time Curve ◽  
Mixed Inhibition

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.

scholarly journals The effects of oral administration of Cola nitida on the pharmacokinetic profile of metoclopramide in rabbits

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Cecilia Nwadiuto Amadi ◽  
Wisdom Izuchukwu Nwachukwu
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Oral Administration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Cola Nitida

Abstract Background Cola nitida is commonly chewed in many West African cultures to ease hunger pangs and sometimes for their stimulant and euphoriant qualities. Metoclopramide is a known substrate for P-gp, SULT2A1 and CYP2D6 and studies have revealed that caffeine- a major component of Cola nitida can induce P-glycoprotein (P-gp), SULT2A1 and SULT1A1, hence a possible drug interaction may occur on co-administration. The aim of this study was to investigate the pharmacokinetic interactions of Cola nitida and metoclopramide in rabbits. Methods The study was performed in two stages using five healthy male rabbits with a 1-week washout period between treatments. Stage one involved oral administration of metoclopramide (0.5 mg/kg) alone while in the second stage, metoclopramide (0.5 mg/kg) was administered concurrently with Cola nitida (0.7 mg/kg). Blood samples were collected after each stage at predetermined intervals and analyzed for plasma metoclopramide concentration using HPLC. Results Compared with control, the metoclopramide/Cola nitida co-administration produced a decrease in plasma concentration of metoclopramide at all the time intervals except at the 7th hour. The following pharmacokinetic parameters were also decreased: area under the curve (51%), peak plasma concentration (39%), half-life (51%); while an increase in elimination rate constant (113%) and clearance rate (98%) were noted indicating rapid elimination of the drug. A minimal decrease in absorption rate (10%) was also observed. Conclusions The results of this study reveal a possible herb-drug interaction between Cola nitida and metoclopramide.

Nanoparticle entrapped docetaxel (CPC634) enhances intratumoral docetaxel exposure compared to conventional docetaxel (Cd) in patients with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3096-3096 ◽  
Author(s):  
Florence Atrafi ◽  
Ruben A.G. van Eerden ◽  
Marte A.M. van Hylckama Vlieg ◽  
Esther Oomen De Hoop ◽  
Peter de Bruijn ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Mixed Model ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Mixed Model Analysis ◽  
Plasma Pharmacokinetics ◽  
Tumor Biopsies ◽  
To Receive

3096 Background: Failure or resistance to chemotherapy may be caused by sub‐therapeutic intratumoral drug levels. Nanomedicine aim to improve intratumoral drug exposure. CPC634 is a nanoparticle entrapping docetaxel. We hypothesized that CPC634 increases intratumoral docetaxel exposure. Methods: In this randomized cross-over study we assessed intratumoral and plasma pharmacokinetics (PK) of docetaxel after intravenous administration of CPC634 and conventional docetaxel (Cd). The study was powered to identify an 25% increase in intratumoral docetaxel exposure of CPC634 relative to Cd. Patients (≥18 years) were randomized to receive 75 mg/m2 CPC634 in cycle 1 and Cd in cycle 2 or vice versa. After drug administration, patients underwent tumor biopsies during both cycles. Total docetaxel was determined for both drugs and released docetaxel for CPC634 in tumor tissue and in plasma with a validated LC-MS/MS method. PK data were analyzed with mixed model analysis. Results: Sixteen evaluable patients were included. Intratumoral PK revealed a 323% (95% CI: 148,621) higher total docetaxel (p < 0.001) for CPC634. Released docetaxel for CPC634 was comparable to total docetaxel levels for Cd (95% CI: -35-,67) (p = 0.43). Plasma released docetaxel for CPC634 exhibited an 89% (95% CI: 86, 91) lower (p < 0.001) peak plasma concentration (Cmax) and 81% (95% CI: 46, 125) higher (p < 0.001) area under the curve (AUC) relative to Cd. Conclusions: CPC634 resulted in higher intratumoral total docetaxel and comparable released docetaxel levels relative to total docetaxel for Cd. CPC634 had a favorable plasma PK profile with a lower Cmax and prolonged higher systemic exposure relative to Cd. These results indicate that CPC634 could improve intratumoral docetaxel exposure compared to Cd. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in patients with platinum resistant ovarian cancer (NCT03742713) are currently ongoing.

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

Pharmacology ◽  
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.

scholarly journals Physostigmine: A Plant Alkaloid Isolated from Physostigma venenosum: A Review on Pharmacokinetics, Pharmacological and Toxicological Activities

2020 ◽  
Vol 10 (1-s) ◽  
pp. 187-190 ◽  
Author(s):  
Gaber El-Saber Batiha ◽  
Luay M. Alkazmi ◽  
Eman H. Nadwa ◽  
Eman K. Rashwan ◽  
Amany Magdy Beshbishy ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Biological Activities ◽  
Peak Plasma Concentration ◽  
Therapeutic Index ◽  
Tricyclic Antidepressant ◽  
Ache Inhibitor ◽  
Short Life Span ◽  
Perennial Shrub ◽  
Butyrylcholinesterase Inhibitor ◽  
Pharmaceutical Molecules

Medicinal plants have been documented as an important source for discovering new pharmaceutical molecules that have been used to treat serious diseases. Strikingly, previous reports stated that natural products and their derived compounds exhibit lesser side effects and improved efficacy than other synthetic counterparts. Physostigmine, a parasympathomimetic plant alkaloid isolated from the West African perennial shrub Physostigma venenosum, it shows a narrow therapeutic index and a short life span, despite its ability to penetrate the blood-brain barrier (BBB). It is a widely known reversible butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) inhibitor and has been documented to treat various ailments such as Alzheimer’s disease. Pharmacologically, physostigmine was first reported as an antidote for atropine scopolamine and belladonna alkaloids toxicity. Recently, it has been documented as a therapy for treating several ailments including glaucoma, myasthenia gravis and the intoxication caused by tricyclic antidepressant overdoses, anti-histamines, antipsychotics, and benzodiazepines. Physostigmine has been reported to be absorbed from the gastrointestinal tract and showed short half-life, as, after the oral administration of 2 mg of physostigmine salicylate, the peak plasma concentration reached to 30 minutes. This review examines the biological activities, pharmacokinetics, and toxicity of physostigmine extracted from P. venenosum. Keywords: Physostigma venenosum, Physostigmine, pharmacological activities, acetylcholinesterase and butyrylcholinesterase inhibitor.

scholarly journals Effect of ritonavir on pharmacokinetics of antimalarial drug combinations in rats

2019 ◽  
Vol 10 (3) ◽  
pp. 2477-2486
Author(s):  
Sunitha G N ◽  
Satyavati Dulipala D ◽  
Girish Gudi
Keyword(s):  
Drug Interaction ◽  
Antimalarial Drug ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Current Treatment ◽  
Drug Combinations ◽  
World Health ◽  
Sprague Dawley ◽  
Artemisinin Derivatives

The current treatment for Human Immunodeficiency Virus (HIV) patients coinfected with malaria involves the coadministration of antimalarial and antiretroviral (ARV) drugs. The World Health Organization (WHO) recommends artemisinin-based therapy for malaria that usually consists of artemether, artesunate or dihydroartemisinin with non-artemisinin derivatives such as amodiaquine, lumefantrine and mefloquine.  Protease inhibitors (PI) such as ritonavir contribute to the improved health of HIV-positive individuals, and the inclusion of ritonavir in antiretroviral regimens is common in clinical practice. Ritonavir is a potent inhibitor of human CYP3A4, which is the primary enzyme involved in the metabolism of many of artemisinin-based drugs, as well as amodiaquine and proguanil.  Upon co-administration, ritonavir can potentially influence the metabolism and thus increase the systemic exposure of these drugs. In order to understand this pharmacokinetic (PK) drug interaction, the current work evaluated the effect of ritonavir (50 mg/kg orally) on the PK of antimalarial drug combinations in Sprague Dawley (SD) rats. When co-administered with ritonavir, the exposure (AUC) of the antimalarial drugs artemether, artesunate and proguanil was increased by approximately 3.5-fold. Correspondingly, peak plasma concentrations (Cmax) of these drugs increased as well. There was no apparent influence of ritonavir on the PK of lumefantrine, amodiaquine and atovaquone. This study demonstrates the potential influence of ritonavir on the pharmacokinetics of at least some anti-malarial drugs, likely a result of inhibition of CYP3A. Further evaluation of clinically relevant drug interaction in humans may be warranted to ensure safe and effective use of anti-malarial and anti-HIV drugs concomitantly.

scholarly journals Pharmacokinetics, Safety, and Tolerability of Intravenous Durlobactam and Sulbactam in Subjects with Renal Impairment and Healthy Matched Control Subjects

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
John O’Donnell ◽  
Richard A. Preston ◽  
Grigor Mamikonyan ◽  
Emily Stone ◽  
Robin Isaacs
Keyword(s):  
Renal Impairment ◽  
Healthy Subjects ◽  
Peak Plasma ◽  
Severe Renal Impairment ◽  
Peak Plasma Concentration ◽  
Phase 1 ◽  
Systemic Exposure ◽  
Moderate Renal Impairment ◽  
Renal Elimination ◽  
Tolerability Profile

ABSTRACT Sulbactam-durlobactam is being developed for the treatment of infections caused by Acinetobacter baumannii, including those caused by multidrug- and carbapenem-resistant isolates. This was a phase 1 study to evaluate the effects of various degrees of renal impairment, including subjects with end-stage renal disease (ESRD) on hemodialysis (HD), on the pharmacokinetics and safety profile of durlobactam (also known as ETX2514) and sulbactam after single intravenous (i.v.) dose administration. For healthy subjects and those with mild or moderate renal impairment (RI), single 1,000-mg doses each of durlobactam and sulbactam via a 3-h i.v. infusion were administered, and for severe renal impairment, 500-mg doses were administered. For subjects with ESRD and HD, 500-mg i.v. doses each of durlobactam and sulbactam were administered post-HD and pre-HD, with a 1-week washout between doses. Among 34 subjects, decreasing renal function increased systemic exposure (peak plasma concentration [Cmax] and area under the concentration-time curve [AUC]) to durlobactam and sulbactam in a generally linear manner. In healthy subjects and in those with mild or moderate renal impairment, the majority of durlobactam and sulbactam was excreted in the urine, while approximately 40% or less was excreted in urine in subjects with severe renal impairment or ESRD. In subjects with ESRD, hemodialysis was effective at removing both durlobactam and sulbactam from plasma. Renal impairment had no effect of the safety/tolerability profile of durlobactam and sulbactam. In summary, RI and ESRD had a predictable effect on the pharmacokinetic (PK) profile of durlobactam and sulbactam with no adverse effects on the safety/tolerability profile. Durlobactam and sulbactam are cleared to a similar extent by renal elimination and are impacted similarly by renal impairment. The results from this study have been used with population PK modeling and nonclinically derived PK/PD (pharmacodynamic) exposure targets to establish dosage recommendations for durlobactam and sulbactam in patients with various degrees of RI. The dosing regimen of durlobactam-sulbactam will require adjustment in patients with severe renal insufficiency and in those with ESRD.

Pharmacokinetics and Haemostatic Status During Consecutive Infusions of Recom binant Tissue-Type Plasminogen Activator in Patients with Acute Myocardial Infarction

1989 ◽  
Vol 61 (03) ◽  
pp. 497-501 ◽  
Author(s):  
E Seifried ◽  
P Tanswell ◽  
D Ellbrück ◽  
W Haerer ◽  
A Schmidt
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Plasminogen Activator ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Precise Control ◽  
Type Plasminogen Activator

SummaryPharmacokinetics and systemic effects of recombinant tissue type plasminogen activator (rt-PA) were determined during coronary thrombolysis in 12 acute myocardial infarction patients using a consecutive intravenous infusion regimen. Ten mg rt-PA were infused in 2 minutes resulting in a peak plasma concentration (mean ±SD) of 3310±950 ng/ml, followed by 50 mg in 1 h and 30 mg in 1.5 h yielding steady state plasma levels of. 2210±470 nglml and 930±200 ng/ml, respectively. All patients received intravenous heparin. Total clearance of rt-PA was 380±74 ml/min, t,½α was 3.6±0.9 min and t,½β was 16±5.4 min.After 90 min, in plasma samples containing anti-rt-PA-IgG to inhibit in vitro effects, fibrinogen was decreased to 54%, plasminogen to 52%, α2-antiplasmin to 25%, α2-macroglobulin to 90% and antithrombin III to 85% of initial values. Coagulation times were prolonged and fibrin D-dimer concentrations increased from 0.40 to 2.7 μg/ml. It is concluded that pharmacokinetics of rt-PA show low interpatient variability and that its short mean residence time in plasma allows precise control of therapy. Apart from its moderate effect on the haemostatic system, rt-PA appears to lyse a fibrin pool in addition to the coronary thrombus.

scholarly journals Nanomedicine Reformulation of Chloroquine and Hydroxychloroquine

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 175
Author(s):  
David M. Stevens ◽  
Rachael M. Crist ◽  
Stephan T. Stern
Keyword(s):  
Safety Evaluation ◽  
Therapeutic Index ◽  
Short Term ◽  
Tissue Concentrations ◽  
History Of ◽  
History Of Use ◽  
Novel Applications ◽  
Therapeutic Doses ◽  
Extensive Clinical Experience ◽  
Higher Doses

The chloroquine family of antimalarials has a long history of use, spanning many decades. Despite this extensive clinical experience, novel applications, including use in autoimmune disorders, infectious disease, and cancer, have only recently been identified. While short term use of chloroquine or hydroxychloroquine is safe at traditional therapeutic doses in patients without predisposing conditions, administration of higher doses and for longer durations are associated with toxicity, including retinotoxicity. Additional liabilities of these medications include pharmacokinetic profiles that require extended dosing to achieve therapeutic tissue concentrations. To improve chloroquine therapy, researchers have turned toward nanomedicine reformulation of chloroquine and hydroxychloroquine to increase exposure of target tissues relative to off-target tissues, thereby improving the therapeutic index. This review highlights these reformulation efforts to date, identifying issues in experimental designs leading to ambiguity regarding the nanoformulation improvements and lack of thorough pharmacokinetics and safety evaluation. Gaps in our current understanding of these formulations, as well as recommendations for future formulation efforts, are presented.

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