Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, and Humans

El‐Kattan, Ayman; Hurst, Susan; Brodfuehrer, Joanne; Loi, Cho‐Ming

doi:10.1002/9781118067598.ch16

Cited by 7 publications

(7 citation statements)

References 108 publications

(117 reference statements)

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“…The recognition motif for transport appears to be strict, as a considerably smaller fraction of the dose was absorbed for the structurally similar analog 7a . Owing to their small molecular weight and hydrophilic nature, paracellular absorption may be another route for the dicarboxylates to achieve moderate absorption . Similar and modest fa values were achieved after oral administration of compound 1 (racemic mixture) or 1a (single enantiomer), suggesting a passive mode of absorption such as paracellular for some of the analogues.…”

Section: Discussionmentioning

confidence: 85%

“…Owing to their small molecular weight and hydrophilic nature, paracellular absorption may be another route for the dicarboxylates to achieve moderate absorption. 15 Similar and modest fa values were achieved after oral administration of compound 1 (racemic mixture) or 1a (single enantiomer), suggesting a passive mode of absorption such as paracellular for some of the analogues. Renal clearance for most analogues evaluated in vivo was greater than rat GFR, implying active renal secretion, although no specific carriers were identified in this study.…”

Section: ■ Discussion and Conclusionmentioning

confidence: 93%

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Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

et al. 2016

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Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate 1a (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to 4a (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound 4a was used to demonstrate dose-dependent inhibition of radioactive [(14)C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations.

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Section: Discussionmentioning

confidence: 85%

Section: ■ Discussion and Conclusionmentioning

confidence: 93%

Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

et al. 2016

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“…Active uptake may also play a role in gut absorption of 2 via intestinal solute carriers, such as NaDC1 31 . Due to its hydrophilicity and low molecular weight, paracellular absorption cannot be ruled out as another potential mechanism for oral absorption of 2 32 33 .…”

Section: Discussionmentioning

confidence: 99%

Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5)

Huard

Brown²,

Jones³

et al. 2015

Sci Rep

131

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Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.

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“…It is worth noting that a number of vaccines can enter the gastrointestinal tract during nasal immunization ( 56 , 57 ). A previous study developed a sheep model to detect the efficacy of nasal vaccine administration.…”

Section: Discussionmentioning

confidence: 99%

Comparison of oral and nasal immunization with inactivated porcine epidemic diarrhea virus on intestinal immunity in piglets

Zhang

Wang

et al. 2020

Exp Ther Med

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Porcine epidemic diarrhea virus (PEDV) has proven to be a major problem for the porcine industry worldwide. Conventional injectable vaccines induce effective systemic immune responses but are less effective in preventing PEDV at mucosal invasion sites, including the nasal or oral mucosa. Additionally, antigens delivered orally are easily degraded. Nasal immunization induces intestinal mucosal immune responses, which can aid in blocking viral invasion, and requires fewer antigen inoculation doses. Therefore, nasal immunizations are considered to be a potential approach to overcome viral infections. In the present study, nasal immunization of piglets was performed using inactivated PEDV combined with Bacillus subtilis as an immunopotentiator and the efficacy of nasal immunization was assessed. The results demonstrated that compared with oral immunization, piglets from the nasal immunization group exhibited higher levels of neutralizing antibodies (P<0.01) in the intestine, PEDV-specific immunoglobulin (Ig)G (P<0.01) in serum and PEDV-specific secretory IgA (SIgA) in saliva (P<0.01) and nasal secretions (P<0.01). An increased number of intestinal CD3 + T cells, IgA-secreting cells and intraepithelial lymphocytes (P<0.05) were also observed. Furthermore, the protein expression levels of interleukin-6 and interferon-γ, relative to the control PEDV infection, were also significantly elevated (P<0.05). The results of the present study indicate that nasal immunization is more effective at inducing the intestinal mucosal immune response, and provide new insights into a novel vaccination strategy that may be used to decrease the incidence of PEDV infections.

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Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, and Humans

Cited by 7 publications

References 108 publications

Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5)

Comparison of oral and nasal immunization with inactivated porcine epidemic diarrhea virus on intestinal immunity in piglets

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