The road map to oral bioavailability: an industrial perspective

Thomas, V. Hayden; Bhattachar, Shobha; Hitchingham, Linda; Zocharski, Philip; Naath, Maryanne; Surendran, Narayanan; Stoner, Chad L.; El‐Kattan, Ayman

doi:10.1517/17425255.2.4.591

Cited by 152 publications

(103 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One method to improve tumor imaging is to improve the bioavailability 31 of the dye conjugate. A piperazine unit is common in many drugs, 32 so we incorporated a piperazine linker with the goal of increasing bioavailability 33 of the dye conjugate.…”

Section: Discussion and Summarymentioning

confidence: 99%

Targeting tumor hypoxia with 2-nitroimidazole-indocyanine green dye conjugates

Xu¹,

Zanganeh²,

Mohammad³

et al. 2013

J. Biomed. Opt

View full text Add to dashboard Cite

Abstract. Tumor hypoxia is a major indicator of treatment resistance to chemotherapeutic drugs, and fluorescence optical tomography has tremendous potential to provide clinically useful, functional information by identifying tumor hypoxia. The synthesis of a 2-nitroimidazole-indocyanine green conjugate using a piperazine linker (piperazine-2-nitroimidazole-ICG) capable of robust fluorescent imaging of tumor hypoxia is described. In vivo mouse tumor imaging studies were completed and demonstrate an improved imaging capability of the new dye relative to an earlier version of the dye that was synthesized with an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG). Mouse tumors located at imaging depths of 1.5 and 2.0 cm in a turbid medium were imaged at various time points after intravenous injection of the dyes. On average, the reconstructed maximum fluorescence concentration of the tumors injected with piperazine-2-nitroimidazole-ICG was twofold higher than that injected with ethanolamine-2-nitroimidazole-ICG within 3 h postinjection period and 1.6 to 1.7 times higher beyond 3 h postinjection. The untargeted bis-carboxylic acid ICG completely washed out after 3 h postinjection. Thus, the optimal window to assess tumor hypoxia is beyond 3 h postinjection. These findings were supported with fluorescence images of histological sections of tumor samples and an immunohistochemistry technique for identifying tumor hypoxia.

show abstract

Section: Discussion and Summarymentioning

confidence: 99%

Targeting tumor hypoxia with 2-nitroimidazole-indocyanine green dye conjugates

Xu¹,

Zanganeh²,

Mohammad³

et al. 2013

J. Biomed. Opt

View full text Add to dashboard Cite

show abstract

“…This is due to the larger numbers of highly-absorbed compounds amongst the marketed drugs that constitute the datasets 7,8 . compounds with low absorption due to solubility issues 11 . Imbalanced datasets are a problem for modelling.…”

Section: Introductionmentioning

confidence: 99%

Coping with Unbalanced Class Data Sets in Oral Absorption Models

Newby

Freitas

Ghafourian

2013

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Class imbalance occurs frequently in drug discovery datasets. In oral absorption datasets, in the literature, there are considerably more of highly-absorbed compounds compared with poorly-absorbed compounds. This produces models that are biased towards highly-absorbed compounds which lack generalization to industry settings where more early stage drug candidates are poorly-absorbed. This paper presents two strategies to cope with unbalanced class datasets: Under-sampling the majority high absorption class and misclassification costs using classification decision trees. The published dataset by Hou et al (2007), which contained percentage human intestinal absorption of 645 drug and drug-like compounds, was used for the development and validation of classification trees using C&RT analysis. The results indicate that under-sampling the majority class, highly-absorbed compounds, leads to a balanced distribution (50:50) training set which can achieve better accuracies for poorlyabsorbed compounds, whereas the biased training set achieved higher accuracies for highlyabsorbed compounds. The use of misclassification costs resulted in improved class predictions, when applied to reduce false positives or false negatives. Moreover, it was shown that the classical overall accuracy measure used in many publications is particularly misleading in the case of unbalanced datasets and more appropriate measures presented here may be used for a more realistic assessment of the classification models' performance. Thus, these strategies offer improvements to cope with unbalanced class datasets to obtain classification models applicable in industry.

show abstract

“…10 It has been observed that several agents enhance the bioavailability of these drugs, which in turn increase their therapeutic potential. 11,12 In the present study, pharmacokinetics profile of paclitaxel was explored specially emphasizing in the pre-treatment with curcumin which causes inhibition of CYP3A4 and P-gp activities.…”

Section: Resultsmentioning

confidence: 99%

Enhancement of Paclitaxel Oral Bioavailability in Swiss Mice by Four Consecutive Days of Pre-Treatment with Curcumin

Sharma¹,

Magotra²,

Nandi³

et al. 2017

IJPER

View full text Add to dashboard Cite

Objective: Poor water solubility, P-glycoprotein (P-gp) efflux property and substrate of CYP3A lead to low oral bioavailability that limit the oral use of paclitaxel, a key anticancer drug. Though several formulation approaches were tried to combat this low absorption profile but effect of pre-treatment with curcumin, a naturally occurring CYP3A and P-gp inhibitor on augmentation of paclitaxel plasma level is not reported till now. Therefore, the objective of the present study is to asses any change in oral pharmacokinetics of paclitaxel. Materials and Methods: curcumin was administered orally to the Swiss mice at a dose of 100 mg/kg for four days and on the fifth day, pharmacokinetics of paclitaxel was carried out at dose of 35 mg/kg orally alone and curcumin pre-treated animals. Results: There is enhancement of Cmax and AUC by 1.4 to 1.5 fold when compared with oral paclitaxel alone treatment that leads to improve in oral bioavailability of paclitaxel. Conclusion: Curcumin can be an ideal candidate for regular use to improve the bioavailability of paclitaxel followed by decrease in dose related side effects. Furthermore, anticancer effect of Curcumin itself as well as with paclitaxel could clinically manage cancer promisingly.

show abstract

The road map to oral bioavailability: an industrial perspective

Cited by 152 publications

References 97 publications

Targeting tumor hypoxia with 2-nitroimidazole-indocyanine green dye conjugates

Targeting tumor hypoxia with 2-nitroimidazole-indocyanine green dye conjugates

Coping with Unbalanced Class Data Sets in Oral Absorption Models

Enhancement of Paclitaxel Oral Bioavailability in Swiss Mice by Four Consecutive Days of Pre-Treatment with Curcumin

Contact Info

Product

Resources

About