scholarly journals Comparative Study of the Effects of Antituberculosis Drugs and Antiretroviral Drugs on Cytochrome P450 3A4 and P-Glycoprotein

2014 ◽  
Vol 58 (6) ◽  
pp. 3168-3176 ◽  
Author(s):  
Yasuhiro Horita ◽  
Norio Doi
Keyword(s):  
Cytochrome P450 ◽  
Mdck Cells ◽  
Inhibitory Effect ◽  
Antiretroviral Drugs ◽  
Aminosalicylic Acid ◽  
P Glycoprotein ◽  
Heparg Cells ◽  
Group 5 ◽  
Almost All

ABSTRACTPredicting drug-drug interactions (DDIs) related to cytochrome P450 (CYP), such as CYP3A4 and one of the major drug transporters, P-glycoprotein (P-gp), is crucial in the development of future chemotherapeutic regimens to treat tuberculosis (TB) and TB/AIDS coinfection cases. We evaluated the effects of 30 anti-TB drugs, novel candidates, macrolides, and representative antiretroviral drugs on human CYP3A4 activity using a commercially available screening kit for CYP3A4 inhibitors and a human hepatocyte, HepaRG. Moreover, in order to estimate the interactions of these drugs with human P-gp, screening for substrates was performed. For some substrates, P-gp inhibition tests were carried out using P-gp-expressing MDCK cells. As a result, almost all the compounds showed the expected effects on human CYP3A4 both in thein vitroscreening and in HepaRG cells. Importantly, the unproven mechanisms of DDIs caused by WHO group 5 drugs, thioamides, andp-aminosalicylic acid were elucidated. Intriguingly, clofazimine (CFZ) exhibited weak inductive effects on CYP3A4 at >0.25 μM in HepaRG cells, while an inhibitory effect was observed at 1.69 μM in thein vitroscreening, suggesting that CFZ autoinduces CYP3A4 in the human liver. Our method, based on one of the pharmacokinetics parameters in humans, provides more practical information associated with not only DDIs but also with drug metabolism.

scholarly journals In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qun Zhang ◽  
Zengqiang Qu ◽  
Yanqing Zhou ◽  
Jin Zhou ◽  
Junwei Yang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Liver Microsomes ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Drug Drug Interaction ◽  
Dose Dependent

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6

2021 ◽  
Vol 36 (4) ◽  
pp. 259-270
Author(s):  
Boon Hooi Tan ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Iekhsan Othman ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Performance ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Time Curve ◽  
Clinical Drugs ◽  
Inhibition Potencies ◽  
P450 2D6

Abstract Objectives Glucosamine, chondroitin and diacerein are natural compounds commonly used in treating osteoarthritis. Their concomitant intake may trigger drug–natural product interactions. Cytochrome P450 (CYP) has been implicated in such interactions. Cytochrome P450 2D6 (CYP2D6) is a major hepatic CYP involved in metabolism of 25% of the clinical drugs. This study aimed to investigate the inhibitory effect of these antiarthritic compounds on CYP2D6. Methods CYP2D6 was heterologously expressed in Escherichia coli. CYP2D6–antiarthritic compound interactions were studied using in vitro enzyme kinetics assay and molecular docking. Results The high-performance liquid chromatography (HPLC)-based dextromethorphan O-demethylase assay was established as CYP2D6 marker. All glucosamines and chondroitins weakly inhibited CYP2D6 (IC50 values >300 µM). Diacerein exhibited moderate inhibition with IC50 and K i values of 34.99 and 38.27 µM, respectively. Its major metabolite, rhein displayed stronger inhibition potencies (IC50=26.22 μM and K i =32.27 μM). Both compounds exhibited mixed-mode of inhibition. In silico molecular dockings further supported data from the in vitro study. From in vitro–in vivo extrapolation, rhein presented an area under the plasma concentration-time curve (AUC) ratio of 1.5, indicating low potential to cause in vivo inhibition. Conclusions Glucosamine, chondroitin and diacerein unlikely cause clinical interaction with the drug substrates of CYP2D6. Rhein, exhibits only low potential to cause in vivo inhibition.

scholarly journals Inhibitory Effect of Lygodium Root on the Cytochrome P450 3A Enzyme in vitro and in vivo

2020 ◽  
Vol Volume 14 ◽  
pp. 1909-1919
Author(s):  
Yunfang Zhou ◽  
Ailian Hua ◽  
Quan Zhou ◽  
Peiwu Geng ◽  
Feifei Chen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Inhibitory Effect ◽  
Cytochrome P450 3A

P-Glycoprotein-Mediated Efflux Using a Rapidly Maturing Caco2 Clone (CLEFF4) in Only 5 Days without Requiring Modified Growth Medium

2020 ◽  
Vol 26 (1) ◽  
pp. 151-160
Author(s):  
Andrew Crowe
Keyword(s):  
Oral Absorption ◽  
Mdck Cells ◽  
Target Cells ◽  
Glycoprotein P ◽  
Caco2 Cells ◽  
P Glycoprotein ◽  
New Chemical Entities ◽  
Bidirectional Transport ◽  
Gp Model

In drug discovery it is essential that one of the parameters tested for any new chemical entity is its affinity for human efflux systems, most notably P-glycoprotein (P-gp). These efflux systems affect not only rates of oral absorption but also rates of excretion through the liver, blood–brain barrier, and accumulation in potential target cells that upregulate efflux systems. Current methods to determine drugs’ P-gp transport potential include in vitro bidirectional transport studies, and the two most common cell lines used are Caco2 and MDR1-transfected MDCK models. Caco2 cells are human but slow growing and require more than 3 weeks to mature, while MDCK cells are canine, but when transfected with human P-gp become a rapid model of P-gp affinity. Our laboratory has generated a Caco2 subclone called CLEFF4 that is fully human, yet now approaches the rapid nature of the MDCK model. No special medium is required. We have shown, in as little as 5 days postseeding, high transepithelial electrical resistance values of more than 1000 Ω·cm2 plus P-gp expression more than threefold higher than that of 21-day-old cells. Currently tested drugs included rhodamine 123 (Rh123), vinblastine, and doxorubicin, and all drugs exhibited P-gp-mediated efflux that was inhibited by PSC833. By day 6, bidirectional transport of Rh123 was as potent as that of mature Caco2 cells, for use in comparative P-gp affinity studies. We now have a human P-gp model that is rapid and works without any need for special accelerating medium. We believe this could be a welcome addition to the testing regime of new chemical entities.

The Intracellular Formation of a Mononucleotide of the Anti-Influenza Agent 1,3,4-thiadiazol-2-ylcyanamide (LY217896)

1995 ◽  
Vol 6 (3) ◽  
pp. 127-137 ◽  
Author(s):  
G. M. Birch ◽  
J. M. Colacino ◽  
W. J. Ehlhardt ◽  
J. Balzarini
Keyword(s):  
Mdck Cells ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
Mass Spectral ◽  
Influenza Activity ◽  
A Cell ◽  
Combination Studies ◽  
Hypoxanthine Guanine Phosphoribosyltransferase ◽  
Mouse Model Of Infection

LY217896 is a substituted thiadiazole compound with anti-influenza activity in vitro and in the mouse model of infection. LY297336 is a ribosylated (N-4) derivative of LY217896. A highly polar intracellular metabolite of LY217896 was isolated by HPLC, and mass spectral analysis and treatment of the metabolite with alkaline phosphatase showed that it was a monophosphate (LY307987) derived from LY217896. The formation of LY307987 was inhibited by 43 and 63% when 10 μm of LY217896 was incubated with 100 μM of 8-aminoguanosine (8AGuo) and guanine (Gua), respectively, whereas inosine (Ino) and hypoxanthine (Hx) had no effect on the formation of LY307987. LY217896 inhibited the incorporation of [14C]-Hx into nucleic acids in cells which metabolize LY217896; however, LY217896 did not inhibit the formation of inosine 5′-monophosphate (IMP) from Hx in a cell-free HGPRT (hypoxanthine-guanine phosphoribosyltransferase)-catalysed reaction. Incubation of MDCK cells with 10 μm of LY217896 resulted in an 8-fold increase in the level of intracellular IMP. At 100 μm, neither LY217896 nor LY297336 inhibited inosine 5′-monophosphate dehydrogenase (IMPDH) and only cellular extracts which contained intracellular metabolites of LY217896 inhibited IMPDH. Quantification of the 5-phosphorylribose pyrophosphate (PRPP) levels in BS-C-1, MDCK, and MCN cells showed a positive correlation between PRPP concentration and cellular metabolism of LY217896. Combination studies of LY217896 with 2′,3′-dideoxyinosine (ddlno) or 2′,3′-dideoxyguanosine (ddGuo) showed that LY217896 enhanced the antiretroviral activities of these dideoxynucleosides, which is consistent with an inhibitory effect on IMPDH.

scholarly journals In vitro inhibition of porcine cytochrome P450 by 17β-estradiol and 17α-estradiol

2011 ◽  
Vol 4 (2) ◽  
pp. 78-84 ◽  
Author(s):  
Galia Zamaratskaia ◽  
Martin Rasmussen ◽  
Isabelle Herbin ◽  
Bo Ekstrand ◽  
Vladimir Zlabek
Keyword(s):  
Cytochrome P450 ◽  
Inhibitory Effect ◽  
17Β Estradiol ◽  
Cyp2e1 Activity ◽  
High Concentrations ◽  
Testicular Steroids ◽  
Sexually Mature

In vitro inhibition of porcine cytochrome P450 by 17β-estradiol and 17α-estradiol Sexually mature pigs are known to possess high concentrations of testicular steroids, which have been shown to change the activities of cytochrome P450 in vitro. The aim of the present study was to evaluate the regulation of CYP1A and CYP2E1 activity by the steroids dihydrotestosterone (DHT), 3β-androstenol, 17β-estradiol and 17α-estradiol. Catalytic activities of 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD) were used as markers of CYP1A activities, while p-nitrophenol hydroxylase (PNPH) was used as a marker of CYP2E1 activities. Of the steroids tested, only 17β-estradiol and 17α-estradiol inhibited EROD and MROD activities. This inhibition was observed when a steroid concentration of 100 μM was used, while lower concentrations showed no inhibitory effect. PNPH activities were inhibited only by 100 μM of 17β-estradiol. The significance of these results in vivo is unknown because inhibition was only found when concentrations of estrogens higher than physiological levels were used. Nevertheless, the results provided further evidence on the important role of estrogens in regulation of porcine cytochrome P450 activities.

scholarly journals Inhibitory Effect of Methanolic and Methanolic-Aqueous Mixture Extract of Leaves of Plectranthus neochilus Schltr (Lamiaceae) and Bauhinia rufescens Lam (Fabaceae) on Two Strains of Enterobacteria Producing Beta-lactamases

2020 ◽  
pp. 11-20
Author(s):  
Mamoudou Hamadou ◽  
Bakari Daoudou ◽  
Baane Martin- Paul ◽  
Salamatou Mohamadou ◽  
Djoulde Darman Roger
Keyword(s):  
Escherichia Coli ◽  
Antibacterial Activity ◽  
Proteus Mirabilis ◽  
Inhibitory Effect ◽  
Beta Lactams ◽  
Beta Lactamases ◽  
Aqueous Mixture ◽  
Almost All ◽  
Multiresistant Strain

The objective of the study was to evaluate in vitro inhibitory effect of methanolic and methanolic-aqueous mixture extracts of Plectranthus neochilus Schltr (P. neochilus) and Bauhinia rufescens Lam (B. rufescens) on the growth of Escherichia coli 25922 and Proteus mirabilis. A phytochemical screening was carried out to highlight compounds (phenolic compounds, flavonoids, alkaloids) with antibacterial activity. Then, an antibiogram was Carried out to investigate the enzymes rendering the resistance. Finally, the E-test was used to evaluate the antibacterial activity of the extract mixture. The Screening results showed that both plants contain total phenolics, flavonoids and alkaloids compounds. The antibiogram has made it possible to establish the sensitivity profile of the strains tested with regard to certain antibiotics. The extract mixture showed antibacterial activity on both strains tested. In the present work, the different mixtures of extracts showed an inhibitory effect on Escherichia coli 25922 [a strain sensitive to almost all the antibiotics tested, in particular the three classes: beta-lactams (Ceftazidine, Ceftriaxone, Meropenem), quinolones (Levofloxacin, Ciprofloxacin) and aminoglycosides (Gentamicin, Amikacin)] and on Proteus mirabilis (a multiresistant strain with almost all the antibiotics tested).

scholarly journals A dynamic in-vitro model of the intestinal epithelium for the investigation of P-glycoprotein activity

2020 ◽  
Author(s):  
Joana Costa ◽  
Vanessa Almonti ◽  
Ludovica Cacopardo ◽  
Daniele Poli ◽  
Simona Rapposelli ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Therapeutic Effects ◽  
Protein Activity ◽  
Glycoprotein P ◽  
Phenyl Derivative ◽  
Natural Substances ◽  
P Glycoprotein ◽  
Pre Treatment ◽  
Vitro Model

Abstract Multidrug resistance is still an obstacle for chemotherapeutic treatments. One of the proteins involved in this phenomenon is the P-glycoprotein, P-gp, which is known to be responsible for the efflux of therapeutic substances from the cell cytoplasm. To date, the identification of a drug that can efficiently inhibit P-gp activity remains a challenge, nevertheless some studies have identified natural compounds suitable for that purpose. Amongst them, curcumin has shown an inhibitory effect on the protein in in vitro studies using Caco-2 cells.To understand if physiological flow can modulate membrane protein activity, we studied the uptake of a P-gp substrate under static and dynamic conditions. Caco-2 cells were cultured in bioreactors and in Transwells and the basolateral transport of Rhodamine-123 assessed in the two systems as a function of P-gp activity. Experiments were performed with and without pre-treatment of the cells with an extract of curcumin or an arylmethyloxy-phenyl derivative to evaluate the inhibitory effect of the natural substance with respect to a synthetic compound.The results indicated that the P-gp activity of the cells cultured in the bioreactors was intrinsically lower, and that the effect of both natural and synthetic inhibitors was up modulated by the presence of flow. Our study underlies the fact that the use of more sophisticated and physiologically relevant in vitro models can bring new insights on the therapeutic effects of natural substances such as curcumin.

Sign in / Sign up

Export Citation Format

Share Document