Quantitative Evaluation of PEPT1 Contribution to Oral Absorption of Cephalexin in Rats

Hironaka, Takanori; Itokawa, Shota; Ogawara, Ken Ichi; Higaki, Kazutaka; Kimura, Takeshi

doi:10.1007/s11095-008-9703-3

Cited by 24 publications

(16 citation statements)

References 54 publications

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“…By maintaining sufficient contact with epithelial cells of the duodenum, jejunum, and ileum, the passive absorption of GlySar may be increased in Pept1 knockout mice, thereby diminishing the "apparent" role of intestinal PEPT1 in drug absorption. Although speculative, this reasoning is in agreement with the findings of Hironaka et al (2009), who reported that PEPT1 contributed to one-half of the total absorption of cephalexin. These authors also noted that, during simulation studies, an 83% bioavailability would be expected for cephalexin in the absence of PEPT1 function because of a compensatory passive diffusion.…”

Section: In Vivo Oral Absorption and Disposition Of Glycylsarcosinesupporting

confidence: 91%

Effect of Dose Escalation on the In Vivo Oral Absorption and Disposition of Glycylsarcosine in Wild-Type andPept1Knockout Mice

Jappar¹,

Hu²,

Smith³

2011

Drug Metab Dispos

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ABSTRACT:This study evaluated the in vivo absorption and disposition of glycylsarcosine (GlySar), after escalating oral doses, in wild-type and peptide transporter 1 (Pept1) knockout mice. Overall, PEPT1 ablation in mice resulted in significant reductions, in vivo, in the rate and extent of GlySar absorption. The AUC of GlySar was proportional to dose in both genotypes over 1 to 100 nmol/g, with minor decrements at the two highest doses.

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Section: In Vivo Oral Absorption and Disposition Of Glycylsarcosinesupporting

confidence: 91%

Effect of Dose Escalation on the In Vivo Oral Absorption and Disposition of Glycylsarcosine in Wild-Type andPept1Knockout Mice

Jappar¹,

Hu²,

Smith³

2011

Drug Metab Dispos

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“…[266,267]) have been carried out on SLC15 [268] members (previously known as PEPT1 and PEPT2), and responsible e.g. for the intestinal uptake of penicillins [269] and cepaholsporins [270,271].…”

Section: The Importance Of Qsars (Quantitative Structure-activity Relmentioning

confidence: 99%

Control of metabolite efflux in microbial cell factories: current advances and future prospects

Kell¹

2018

Preprint

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The yield and ease of purification of biotechnological products are typically greatly enhanced if they can be secreted into the external medium. Although not universally appreciated, however, small molecule biotechnological products do not ‘float across’ the phospholipid bilayer portion of biological membranes, and thus they need transporters to assist their passage into the extramembrane and extracellular spaces. Some of these transporters may be reversible, equilibrative transporters that might more normally be used for uptake, while others may have an efflux directionality imposed on them via suitable energy coupling mechanisms. Despite the energetic costs of small molecule synthesis, natural evolution does in fact provide a number of mechanisms by which the secretion of such products can actually enhance fitness. Where available these provide useful starting points, and assaying for such activities is crucial. In particular, in a systems biology approach, we first need to identify such/suitable activities before we can seek to increase them. They may then be improved through promoter engineering, via manipulation of control elements, or by directed evolution of the transporter proteins themselves. Modern methods of synthetic biology provide enormous opportunities for all kinds of efflux transporter engineering; they are just beginning to be realised.

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“…We used jejunum region in this study, because the intestinal absorption of cephalexin was site dependent, which is much higher in the upper segment of small intestine than that in the lower segment. 20,21) As shown in Fig. 3, no significant difference in the intestinal transport of cephalexin was observed in the presence of Wellsolve as compared with the control, although there was a slight increase in the transport of cephalexin with the concentration of 1%, 5% and 10% (v/v) Wellsolve.…”

Section: Effect Of Wellsolve On the Transport Of Cf Across The Intestmentioning

confidence: 78%

The Effect of Wellsolve, a Novel Solubilizing Agent, on the Intestinal Barrier Function and Intestinal Absorption of Griseofulvin in Rats

Hamid

Yang

Gao

et al. 2009

Biological & Pharmaceutical Bulletin

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Recently, molecular weights of many drugs and their candidates have been increasing by the progress of combinatorial chemistry and high throughput screening (HTS). Therefore, it is known that water solubility of these drug candidates tended to decrease because of their large molecular size and high lipophilicity. As drug solubility is one of the most important factors affecting the intestinal drug absorption after oral administration, the poor solubility of these drug candidates is one of the most serious problems to achieve the high bioavailability of these drug candidates.Many strategies have been examined to overcome the low water solubility of drugs and their candidates. These strategies include solid dispersion, salt formulation, emulsion and liposomes and pharmaceutical excipients (solubilizing agents).1) Of these strategies, solubilizing agents have been utilized to improve the solubility of poorly water-soluble drugs and their bioavailability (BA) after oral administration. These solubilizing agents were considered inert substances that would be mainly used as diluents, fillers, binders, lubricants, coatings, solvents, dyes, and in the manufacture of drug products. However, the solubilizing agents may sometimes alter the intestinal membrane integrity and affect the function of transporters including P-glycoprotein (P-gp) and peptide transporter (PEPT1) in the intestine. Indeed, our previous study demonstrated that sodium taurocholate (NaTC), a natural surfactant and a bile salt, could increase the intestinal absorption of phenol red, a poorly absorbable compound in rats and cause the intestinal membrane damage as evaluated by the release amount of protein and phospholipid from the intestinal membranes.2,3) In addition, the intestinal absorption of insulin, gentamicin and other hydrophilic drugs was improved in the presence of Labrasol, one of the typical solubilizing agent. [4][5][6] Furthermore, more recently, we found that NaTC and Labrasol at higher concentrations might alter the intestinal barrier functions and increase the intestinal absorption of 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4000 (FD4) in rats. 7)As for the effect of solubilizing agents on the function of transporters, it has been reported that several common excipients could modulate the activity of P-gp, a typical efflux transporter.8) Furthermore, our previous study indicated that Cremophor EL, Tween 80,, polyethyleneglycol (PEGs) and Labrasol also inhibited the function of P-gp in the intestine, thereby reducing the secretory transport of rhodamine123 and other P-gp substrates.9-12) Therefore, it is important to find out a suitable solubilizing agent, which has high potency and no influence on the function of integrity and transporters in the intestine.Based on the background, Wellsolve, a novel solubilizing agent, has recently been developed by Celeste Co., Ltd., although the components of this agent were not disclosed. In the preliminary studies, Wellsolve coul...

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Quantitative Evaluation of PEPT1 Contribution to Oral Absorption of Cephalexin in Rats

Abstract: PEPT1 substantially contributes to oral absorption of cephalexin, around a half of total absorption. However, the function of PEPT1 can be compensated by passive diffusion for cephalexin.

Cited by 24 publications

References 54 publications

Effect of Dose Escalation on the In Vivo Oral Absorption and Disposition of Glycylsarcosine in Wild-Type andPept1Knockout Mice

Effect of Dose Escalation on the In Vivo Oral Absorption and Disposition of Glycylsarcosine in Wild-Type andPept1Knockout Mice

Control of metabolite efflux in microbial cell factories: current advances and future prospects

The Effect of Wellsolve, a Novel Solubilizing Agent, on the Intestinal Barrier Function and Intestinal Absorption of Griseofulvin in Rats

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