Optimizing Oral Bioavailability in Drug Discovery: An Overview of Design and Testing Strategies and Formulation Options

Aungst, Bruce J.

doi:10.1016/j.xphs.2016.12.002

Cited by 118 publications

(71 citation statements)

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“…Drug metabolism is an important procedure closely related to therapeutic effects and multidrug resistance . We found that Bv had little effect on 5‐FU concentration in plasma and liver (Figure A,B) as well as on the concentration of hepatic inactivated metabolite 5‐FUH 2 (Figure C).…”

Section: Discussionmentioning

confidence: 83%

Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway

et al. 2018

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Bevacizumab (Bv) can be used synergistically with fluoropyrimidine‐based chemotherapy to treat colorectal cancer. Whether and how it affects the delivery of fluoropyrimidine drugs is unknown. The present study aimed to explore the effect of Bv on the delivery of 5‐fluorouracil (5‐FU) to tumors and the underlying mechanism from metabolic perspective. Bv enhanced the anti‐tumor effects of 5‐FU in LoVo colon cancer xenograft mice and increased the 5‐FU concentration in tumors without affecting hepatic 5‐FU metabolism. Interestingly, Bv remarkably upregulated thymidine phosphorylase (TP) in tumors, which mediated the metabolic activation of 5‐FU. Although TP is reported to promote angiogenesis and resistance, the combination of Bv and 5‐FU resulted in anti‐angiogenesis and vessel normalization in tumors, indicating that the elevated TP mainly contributed to the enhanced response to 5‐FU. Bv also induced TP upregulation in LoVo cancer cells. Treatment with vascular endothelial growth factor receptor 2 (VEGFR2) antagonist apatinib and VEGFR2 silencing further confirmed TP upregulation. Bv and apatinib both enhanced the cytotoxicity of 5‐FU in LoVo cells, but there was no synergism with adriamycin and paclitaxel. We further demonstrated that the effect of Bv was dependent on VEGFR2 blockade and specificity protein 1 activation via MDM2 inhibition. In summary, Bv enhanced the accumulation of 5‐FU in tumors and the cytotoxicity of 5‐FU via TP upregulation. We provide data to better understand how Bv synergizes with 5‐FU from metabolic perspective, and it may give clues to the superiority of Bv in combination with fluoropyrimidine drugs compared to other chemotherapeutic drugs in colon cancer.

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Section: Discussionmentioning

confidence: 83%

Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway

et al. 2018

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“…Most drugs are administered orally for two major reasons: its convenience to patients and ease of manufacturing oral drugs. Therapeutic agents administered orally have to be adequately available in systemic circulation (orally bioavailable) in order to reach their target receptor/proteins (Mishra et al, 2012;Aungst, 2017). Lipinski proposed a rule, known as 'rule of five' (ro5) used to assess drug-likeness of potential drug molecules.…”

Section: Oral Bioavailability Of the 1hindole-23-dionesmentioning

confidence: 99%

Synthesis and in silico investigation of Schiff base derivatives of 1H-indole-2,3-diones and their Co(II) and Ni(II) complexes as antimicrobial agents

Echekwube¹,

Ukoha²,

Ujam³

et al. 2019

Braz. J. Biol. Sci.

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3-[(2-aminophenyl)imino]-1,3-dihydro-2H-indol-2-one, (Lo), 1,3-phenylenediazanylylidene di (1,3-dihydro-2H-indol-2-one), (Lm) and 1,4-phenylenediazanylylidene di(1,3-dihydro-2H-indol-2-one) (Lp) were synthesized by the reaction of 1H-indole-2,3-dione with benzene-1,2-diamine, benzene-1,3-diamine and benzene-1,4-diamine respectively. The reaction of Lo, Lm and Lp with Co(II) and Ni(II) halides gave the corresponding coordination complexes which were characterized by elemental analysis, molar conductance, infra-red, GC-MS and electronic spectral studies. Docking of the 1H-indole-2,3-diones toward the binding sites of penicillin binding protein and DNA gyrase showed they interacted favourably with the test antibacterial targets at deltaGs range of -2.51 to -5.48 kcal/mol. In accordance to literature report, coordination of cobalt and nickel to the ligands yielded metal complexes which exhibited improved interaction with the protein targets (at deltaGs range of -8.70 to -10.20 kcal/mol). In vitro antimicrobial studies against some microorganisms showed that some of the compounds were active against few Gram negative and Gram positive bacteria. The Lo, Lm and Lp had no activity against any of the test microorganisms but the Co(II) and Ni(II) complexes, showed antibacterial activity. The [Co(Lo)2] and [Ni(Lo)2] complexes generated the least antibacterial response. [Co(Lo)2] was ineffective against E. coli 6 and Staphylococcus sciuri subsp sciuri while Bacillus subtilis was resistant to [Ni(Lo)2] which moderately inhibited E. coli 14 (7 mm). Both compounds indicated zero activity against Pseudomonas aeruginosa. The complex that evoked the highest bactericidal activity were [CoLm]Cl2 and [NiLp]Cl2. The antibiogram activity of [CoLm]Cl2 was found between 20 and 30 mm with E. coli 6 displaying greater sensitivity (30 mm) and S. sciuri the least (20 mm). The activity of [NiLp]Cl2 complex indicate that the activity spectrum of the organisms occurred within 29 and 45 mm range; the least sensitive were E. coli 14 (29 mm) and B. subtilis (29 mm) while the most sensitive was S. sciuri subsp sciuri (45 mm). The two compounds were further studied for minimum inhibitory concentration (MIC) and their binding modes towards the studied protein targets were analyzed. Result indicate that the MIC of 1.25 ug/mL was determined for the complex ([NiLp]Cl2) against S. sciuri subsp sciuri (12 mm) while in case of [CoLm]Cl2, the MIC was 2.5 ug/mL (13 mm) against the same organism. The binding modes predicted for [CoLm]Cl2 and [NiLp]Cl2 identified essential residues necessary for interaction with the studied proteins and which could be targeted during structural/activity optimization.

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“…3,12 However, hydrophobic steroid derivatives have a poor aqueous solubility, 13 resulting in a weak oral bioavailability in several cases. 14 To improve aqueous solubility, hence enhancing the bioavailability of hydrophobic drugs, 15 organic solvents may be introduced in the formulation. Indeed, a study has been realized with RM-133, an ethynylated derivative of the aminosteroid AH-38, to find an appropriate formulation to maximize its bioavailability, 12 but the solubility of RM-133 remained limited and toxicity has also been observed depending on the organic solvent used.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and pharmacokinetic study of poly(ethylene oxide) triazole dendrimers decorated with aminosteroids as anticancer agent

Darveau

Maltais²,

Roy³

et al. 2020

Journal of Polymer Science

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The use of new aminosteroids has shown increased therapeutic efficiency on multiple cancer cell lines. Those molecules are, however, highly hydrophobic, leading to bad pharmacokinetic properties. Dendrimers are excellent candidates to improve PK, especially for absorption and distribution, since their structure can be designed to be water‐soluble. We have the capacity to tailor the particle's size to allow high‐loading capacity. In this article, we managed to enhance aqueous solubility of the aminosteroid AH‐38 by grafting on three generations of poly(ethylene oxide) triazole dendrimers to reach high drug loading values (w/w %). In vitro and in vivo studies were conducted and showed interesting results, such as increased plasma concentration of the free aminosteroid with G1 and G2 nanocarriers over the AH‐38 administrated as a free drug. © 2020 Wiley Periodicals, Inc. J. Polym. Sci. 2020, 58, 654–661

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Optimizing Oral Bioavailability in Drug Discovery: An Overview of Design and Testing Strategies and Formulation Options

Cited by 118 publications

References 50 publications

Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway

Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway

Synthesis and in silico investigation of Schiff base derivatives of 1H-indole-2,3-diones and their Co(II) and Ni(II) complexes as antimicrobial agents

Synthesis and pharmacokinetic study of poly(ethylene oxide) triazole dendrimers decorated with aminosteroids as anticancer agent

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