A pharmacokinetic comparison of homodimer ARB-92 and heterodimer ARB-89: novel, potent antimalarial candidates derived from 7β-hydroxyartemisinin

Avery, Bonnie A.; Pabbisetty, Deepthi; Li, Lie; Sharma, Abhisheak; Gundluru, Mahesh K.; Chittiboyina, Amar G.; Williamson, John S.; Avery, Mitchell A.

doi:10.1007/s40005-017-0352-6

Cited by 6 publications

(6 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The IC 50 of CEL for the inhibition of the metabolism of REP was determined by GraphPad Prism 5.01 (GraphPad Software, San Diego, CA, USA) according to the following Hill equation:normaly=Min+Max−Min1+(xIC50)−normalP. Analytical data were acquired and processed using the LC Solution Software (Version 1.25; Shimadzu Co.). Non-compartmental analysis was conducted to estimate pharmacokinetic parameters such as total area under plasma concentration versus time curve from time zero to infinity (AUC inf ), total area under plasma concentration versus time curve from time zero to time of last sampling (AUC last ), and terminal half-life ( t 1/2 ) using the NCA200 and 201 models of WinNonlin software (Version 3.1; Certara USA Inc., Princeton, NJ, USA) [32]. Peak plasma concentration ( C max ) and time to reach C max ( T max ) were directly read from the observed data.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Evaluation of Metabolic Drug Interactions between Repaglinide and Celecoxib by a Bioanalytical HPLC Method for Their Simultaneous Determination with Fluorescence Detection

et al. 2019

View full text Add to dashboard Cite

Since diabetes mellitus and osteoarthritis are highly prevalent diseases, combinations of antidiabetic agents like repaglinide (REP) and non-steroidal anti-inflammatory drugs (NSAID) like celecoxib (CEL) could be commonly used in clinical practice. In this study, a simple and sensitive bioanalytical HPLC method combined with fluorescence detector (HPLC-FL) was developed and fully validated for simultaneous quantification of REP and CEL. A simple protein precipitation procedure and reversed C18 column with an isocratic mobile phase (mixture of ACN and pH 6.0 phosphate buffer) were employed for sample preparation and chromatographic separation. The fluorescence detector was set at a single excitation/emission wavelength pair of 240 nm/380 nm. The linearity (10–2000 ng/mL), accuracy, precision, extraction recovery, matrix effect, and stability for this method were validated as per the current FDA guidance. The bioanalytical method was applied to study pharmacokinetic interactions between REP and CEL in vivo, successfully showing that concurrent administration with oral REP significantly altered the pharmacokinetics of oral CEL. Furthermore, an in vitro metabolism and protein binding study using human materials highlighted the possibility of metabolism-based interactions between CEL and REP in clinical settings.

show abstract

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Evaluation of Metabolic Drug Interactions between Repaglinide and Celecoxib by a Bioanalytical HPLC Method for Their Simultaneous Determination with Fluorescence Detection

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The peaks of the analytes at the LLOQ should be discrete, identifiable, and reproducible with acceptable precision (<20%) and accuracy (within 80-120%). The extraction recovery, matrix effect, dilution integrity, and stability (under bench-top, freeze-thaw, post-preparative, and long-term conditions) in addition to the intra-assay (five different samples) and inter-assay (five different runs) precision and accuracy for each analyte were determined at the LLOQ and three different QC levels as described in the US FDA guidelines and in previous studies [11,[17][18][19]].…”

Section: Bioanalytical Methods Validationmentioning

confidence: 99%

“…Blood (approximately 200 µL) was collected in heparin pre-treated microcentrifuge tubes via the femoral artery at 0, 1, 5, 15, 30, 60, 120, 180, 240, 360, 480, and 1200 min after the intravenous dose and at 0, 5, 15, 30, 60, 120, 150, 180, 240, 360, 480, and 1200 min after the oral dose. Following centrifugation of the blood samples at 3000× g at 4 • C for 10 min [19], 100 µL aliquots of plasma were stored at −80 • C.…”

Section: In Vivo Pharmacokinetic Study In Ratsmentioning

confidence: 99%

In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole

et al. 2019

View full text Add to dashboard Cite

Dutasteride (DUT) is a selective, potent, competitive, and irreversible inhibitor of both type-1 and type-2 5α-reductase (5AR) commonly used in the treatment of benign prostatic hyperplasia and androgenetic alopecia. In the present study, we developed a simple and sensitive high-performance liquid chromatography with fluorescence detection (HPLC-FL) method for simultaneous determination of DUT and its major active metabolite, 6β-hydroxydutasteride (H-DUT). Next, the pharmacokinetic interactions of DUT with ketoconazole (KET), a potent CYP3A inhibitor, were comprehensively investigated. In vivo rat intravenous and oral studies revealed that the pharmacokinetics of DUT and H-DUT were significantly altered by the co-administration of KET. Furthermore, the in vitro microsomal metabolism, blood distribution, and protein-binding studies suggest that the altered pharmacokinetics of DUT could be attributed primarily to the inhibition of the DUT metabolism by KET. To the best of our knowledge, this is the first study to show the drug interaction potential of DUT with azole antifungal drugs including KET, together with a newly developed HPLC-FL method for the simultaneous quantification of DUT and H-DUT.

show abstract

“…The antiplasmodial activity of ferrocene‐containing dimer 24a (Figure , IC 50 : 7.2nM) was slightly higher than that of chloroquine (IC 50 : 9.8nM) against CQS 3D7 strain of P falciparum , while introduction of alkyl side chain between artemisinin and ferrocene moieties led to loss of activity ( 24b , IC 50 : 29.6nM) . The carbamate dimer 25a (ARB‐89) and the carbonate analog 25b (ARB‐92) were not only showed great potency (IC 50 ≤ 0.50nM) against P falciparum infected human red blood cells, but also demonstrated excellent in vivo antimalarial activity: in the P berghei N ‐infected male CD1 mice, at a dose of 3.3 mg/kg, the parasitemia suppression of the two dimers was greater than 96% and 99% respectively, both were higher than artesunate (94%) at the same dose . The cytotoxicity study revealed that the two dimers had no cytotoxicity.…”

Section: Artemisinin‐derived Dimers With Miscellaneous Linkersmentioning

confidence: 99%

Artemisinin‐derived dimers and their antimalarial activities

Yang

et al. 2019

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

Malaria is a tropical disease that leads around half a million people to succumb annually. Antimalarial agents such as artemisinin and its derivatives are crucial to malaria treatment; however, the rapid development of drug resistance to clinically used antimalarials is still the major obstacle to effective chemotherapy. To tackle the growing resistance issue, new antimalarial agents are urgently needed. Using artemisinin-derived dimers as pharmacological scaffolds has demonstrated promising antimalarial activity; therefore, rational design of the dimers may provide valuable therapeutic intervention to treat malaria or even drug-resistant malaria. This review emphasized two aspects: (a) different linker-tethered artemisinin-derived dimers with potential antimalarial activity and (b) the structure-activity relationships discussed to provide an insight for rational design of dimers with improved efficiency.

show abstract

A pharmacokinetic comparison of homodimer ARB-92 and heterodimer ARB-89: novel, potent antimalarial candidates derived from 7β-hydroxyartemisinin

Cited by 6 publications

References 20 publications

Pharmacokinetic Evaluation of Metabolic Drug Interactions between Repaglinide and Celecoxib by a Bioanalytical HPLC Method for Their Simultaneous Determination with Fluorescence Detection

Pharmacokinetic Evaluation of Metabolic Drug Interactions between Repaglinide and Celecoxib by a Bioanalytical HPLC Method for Their Simultaneous Determination with Fluorescence Detection

In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole

Artemisinin‐derived dimers and their antimalarial activities

Contact Info

Product

Resources

About