NET occupancy by clomipramine and its active metabolite, desmethylclomipramine, in non-human primates in vivo

2011 ◽  
Vol 216 (2) ◽  
pp. 279-286 ◽  
Author(s):  
Akihiro Takano ◽  
Sangram Nag ◽  
Balázs Gulyás ◽  
Christer Halldin ◽  
Lars Farde
Keyword(s):  
Active Metabolite

scholarly journals P-0177 Effect of Bevacizumab on P-Glycoprotein Activity and on the Pharmacokinetics of Irinotecan and its Main Active Metabolite (SN-38) in Vivo

2012 ◽  
Vol 23 ◽  
pp. iv81
Author(s):  
Jean-Meidi Alili ◽  
Marie-Sophie Noel-Hudson ◽  
Celine Chu ◽  
Chadi Abbara ◽  
Robert Farinotti ◽  
...  
Keyword(s):  
Active Metabolite ◽  
P Glycoprotein

scholarly journals The Mechanism of Action of Cyclophosphamide and Its Consequences for the Development of a New Generation of Oxazaphosphorine Cytostatics

2020 ◽  
Vol 88 (4) ◽  
pp. 42
Author(s):  
Georg Voelcker
Keyword(s):  
Mechanism Of Action ◽  
Active Metabolite ◽  
Dna Alkylation ◽  
In Vivo Metabolism ◽  
Pharmacologically Active ◽  
New Generation ◽  
Anti Tumor Activity ◽  
Oxazaphosphorine Cytostatics

Although cyclophosphamide (CP) has been used successfully in the clinic for over 50 years, it has so far not been possible to elucidate the mechanism of action and to use it for improvement. This was not possible because the basis of the mechanism of action of CP, which was found by lucky coincidence, is apoptosis, the discovery of which was honored with the Nobel Prize only in 2002. Another reason was that results from cell culture experiments were used to elucidate the mechanism of action, ignoring the fact that in vivo metabolism differs from in vitro conditions. In vitro, toxic acrolein is formed during the formation of the cytotoxic metabolite phosphoreamidemustard (PAM), whereas in vivo proapoptotic hydroxypropanal (HPA) is formed. The CP metabolites formed in sequence 4-hydroxycyclophosphamide (OHCP) are the main cause of toxicity, aldophosphamide (ALDO) is the pharmacologically active metabolite and HPA amplifies the cytotoxic apoptosis initiated by DNA alkylation by PAM. It is shown that toxicity is drastically reduced but anti-tumor activity strongly increased by the formation of ALDO bypassing OHCP. Furthermore, it is shown that the anti-tumor activity against advanced solid P388 tumors that grow on CD2F1 mice is increased by orders of magnitude if DNA damage caused by a modified PAM is poorly repairable.

Triazene metabolism. III. In vitro cytotoxicity towards M21 cells and in vivo antitumour activity of the proposed metabolites of the antitumour 1-aryl-3,3-dimethyltriazenes

1984 ◽  
Vol 62 (4) ◽  
pp. 396-402 ◽  
Author(s):  
Douglas J. Kohlsmith ◽  
Keith Vaughan ◽  
Stephen J. Luner
Keyword(s):  
Cell Line ◽  
Chemical Stability ◽  
Active Metabolite ◽  
Melanoma Cell Line ◽  
Antitumour Activity ◽  
Metabolic Activation ◽  
In Vitro Cytotoxicity ◽  
Structural Analogues

In vitro cytotoxicity of a series of antitumour triazenes towards the M21 melanoma cell line has been studied. Dimethyltriazenes are structural analogues of 5-(3,3-dimethyl-1-triazeno-)imidazole-4-carboxamide (Dacarbazine) and are inactive, which is consistent with the requirement for metabolic activation. Monomethyltriazenes and hydroxymethyltriazenes, the proposed metabolites of the dimethyltriazenes, are cytotoxic to the M21 cell line. A new series of 4-hydroxy-1,2,3-benzotriazines has been tested for in vitro cytotoxicity. A series of monoalkyltriazenes (Ar∙N=N∙NHR) has been tested for antitumour activity against the P388 lymphoma in vivo. Only monomethyltriazenes had significant antitumour activity, which supports the hypothesis that the monomethyltriazene is the active metabolite of the antitumour dimethyltriazenes. The activity of monomethyltriazenes in vivo is correlated with the chemical stability and t1/2 measurements in pH 7.5 phosphate buffer.

The Intestine As an Important Contributor to Prasugrel Active Metabolite Formation In Vivo

2010 ◽  
Vol 39 (4) ◽  
pp. 565-570 ◽  
Author(s):  
Katsunobu Hagihara ◽  
Miho Kazui ◽  
Hidenori Ikenaga ◽  
Toshihiko Nanba ◽  
Kiichi Fusegawa ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Metabolite Formation ◽  
Important Contributor

scholarly journals Effects of Silymarin on the In Vivo Pharmacokinetics of Simvastatin and Its Active Metabolite in Rats

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1666
Author(s):  
Ying Li ◽  
Yin Wu ◽  
Ya-Jing Li ◽  
Lu Meng ◽  
Cong-Yang Ding ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Compartmental Model ◽  
Elimination Rate ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Simultaneous Quantification ◽  
Concentration Time ◽  
Significant Difference ◽  
In Vivo Pharmacokinetics

Herein, the effect of silymarin pretreatment on the pharmacokinetics of simvastatin in rats was evaluated. To ensure the accuracy of the results, a rapid and sensitive UPLC–MS/MS method was established for simultaneous quantification of simvastatin (SV) and its active metabolite simvastatin acid (SVA). This method was applied for studying the pharmacokinetic interactions in rats after oral co-administration of silymarin (45 mg/kg) and different concentrations of SV. The major pharmacokinetic parameters, including Cmax, tmax, t1/2, mean residence time (MRT), elimination rate constant (λz) and area under the concentration-time curve (AUC0–12h), were calculated using the non-compartmental model. The results showed that the co-administration of silymarin and SV significantly increased the Cmax and AUC0–12h of SVA compared with SV alone, while there was no significant difference with regards to Tmax and t1/2. However, SV pharmacokinetic parameters were not significantly affected by silymarin pretreatment. Therefore, these changes indicated that drug-drug interactions may occur after co-administration of silymarin and SV.

scholarly journals Leflunomide regulates c-Myc expression in myeloma cells through PIM targeting

2019 ◽  
Vol 3 (7) ◽  
pp. 1027-1032 ◽  
Author(s):  
Ralf Buettner ◽  
Corey Morales ◽  
Enrico Caserta ◽  
Estelle Troadec ◽  
Emine G. Gunes ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Myeloma Cells ◽  
Pim Kinases ◽  
Key Points ◽  
Extended Survival

Key Points Teriflunomide, the active metabolite of leflunomide, downregulates c-Myc expression through inhibition of PIM kinases. Leflunomide together with lenalidomide significantly extended survival in an in vivo MM model.

scholarly journals In vivo/ex vivo efficacy of artemether–lumefantrine and artesunate–amodiaquine as first-line treatment for uncomplicated falciparum malaria in children: an open label randomized controlled trial in Burkina Faso

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Moussa Lingani ◽  
Léa Nadège Bonkian ◽  
Isidore Yerbanga ◽  
Adama Kazienga ◽  
Innocent Valéa ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Burkina Faso ◽  
Uncomplicated Malaria ◽  
Active Metabolite ◽  
Ex Vivo ◽  
Controlled Trial ◽  
First Line ◽  
Test Technique ◽  
Ic50 Values

Abstract Background Artemisinin-based combination therapy (ACT) is recommended to improve malaria treatment efficacy and limit drug-resistant parasites selection in malaria endemic areas. 5 years after they were adopted, the efficacy and safety of artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ), the first-line treatments for uncomplicated malaria were assessed in Burkina Faso. Methods In total, 440 children with uncomplicated Plasmodium falciparum malaria were randomized to receive either AL or ASAQ for 3 days and were followed up weekly for 42 days. Blood samples were collected to investigate the ex vivo susceptibility of P. falciparum isolates to lumefantrine, dihydroartemisinin (the active metabolite of artemisinin derivatives) and monodesethylamodiaquine (the active metabolite of amodiaquine). The modified isotopic micro test technique was used to determine the 50% inhibitory concentration (IC50) values. Primary endpoints were the risks of treatment failure at days 42. Results Out of the 440 patients enrolled, 420 (95.5%) completed the 42 days follow up. The results showed a significantly higher PCR unadjusted cure rate in ASAQ arm (71.0%) than that in the AL arm (49.8%) on day 42, and this trend was similar after correction by PCR, with ASAQ performing better (98.1%) than AL (91.1%). Overall adverse events incidence was low and not significantly different between the two treatment arms. Ex vivo results showed that 6.4% P. falciparum isolates were resistant to monodesthylamodiaquine. The coupled in vivo/ex vivo analysis showed increased IC50 values for lumefantrine and monodesethylamodiaquine at day of recurrent parasitaemia compared to baseline values while for artesunate, IC50 values remained stable at baseline and after treatment failure (p > 0.05). Conclusion These findings provide substantial evidence that AL and ASAQ are highly efficacious for the treatment of uncomplicated malaria in children in Burkina Faso. However, the result of P. falciparum susceptibility to the partner drugs advocates the need to regularly replicate such surveillance studies. This would be particularly indicated when amodiaquine is associated in seasonal malaria chemoprophylaxis (SMC) mass drug administration in children under 5 years in Burkina Faso. Trial registration clinicaltrials, NCT00808951. Registered 05 December 2008,https://clinicaltrials.gov/ct2/show/NCT00808951?cond=NCT00808951&rank=1

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