Site of drug absorption after oral administration: Assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract

Masaoka, Yoshie; Tanaka, Yusuke; Kataoka, Makoto; Sakuma, Shinji; Yamashita, Shinji

doi:10.1016/j.ejps.2006.06.004

Cited by 153 publications

(104 citation statements)

References 32 publications

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“…The differences between the in vitro models are much less apparent with highpermeability, noneffluxed compounds such as theophylline, which would have been confirmed as a suitable candidate for MR formulation (González and Straughan, 1994) using data from either Caco-2 cells or ex vivo mouse or human tissues. Lower colonic permeability in humans compared with that in rats has been noted previously (Masaoka et al, 2006) and may typify a more generalized permeability difference between humans and rodents (Kim et al, 2006). This difference may have a physiological basis in that the longer colonic transit time in humans (ϳ24 h compared with ϳ1 h in mouse) provides greater exposure to potentially toxic substances and thus a significantly lower intrinsic permeability coupled to high levels of efflux transporters is likely to be beneficial.…”

Section: Discussionmentioning

confidence: 98%

Investigation of Regional Mechanisms Responsible for Poor Oral Absorption in Humans of a Modified Release Preparation of the α-Adrenoreceptor Antagonist, 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003): The Rational Use of ex Vivo Intestine to Predict in Vivo Absorption

Collett¹,

Stephens²,

Harwood³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Modified release (MR) formulations are used to enhance the safety and compliance of existing drugs by improving their pharmacokinetics. Predicting the likely success of MR formulations is often difficult before clinical studies. A systematic in vitro approach using mouse and human tissues was adopted to rationalize the in vivo pharmacokinetics of 9-and 15-h MR formulations of an ␣-adrenoreceptor antagonist, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003). Immediate release UK-338,003 was well absorbed in humans consistent with moderate Caco-2 cell monolayer permeability. In contrast, 9-and 15-h modified release formulations showed marked reductions in C max (47.1 and 68.9%) and AUC 0-72 (32.6 and 54.0%). Colonic intubation resulted in 81.3 and 73.8% reductions in C max and AUC 0-72 . Mechanistic studies in isolated mouse tissues showed that colonic UK-338,003 permeability (P app < 0.5 ؋ 10 ؊6 cm/s) was at least 40 times lower than that for ileum with marked asymmetry. UK-338,003 was found to be a substrate for P-glycoprotein (PGP) with a weaker interaction for multidrug resistance-associated protein-type transporters in mouse intestine. PGP inhibition dramatically increased colonic UK-338,003 permeability to the levels observed in ileum. Low UK-338,003 apical to basolateral permeability was also observed in ex vivo human distal intestine, but both the asymmetry and increase in permeability after PGP inhibition were significantly lower. In conclusion, the poor absorption of MR UK-338,003 in humans can be explained by a combination of PGP-dependent efflux and low intrinsic permeability in the lower bowel. Regional permeability studies in ex vivo tissues used during drug development can highlight absorption problems in the distal bowel and assess the feasibility of developing successful MR formulations.Oral modified release (MR) formulation can improve the pharmacokinetic and pharmacodynamic properties of a drug and thus lead to both improved patient compliance and safety (Conley et al., 2006). However, predicting the success of MR formulations for a given drug has proved difficult, particularly for drugs with moderate intestinal permeability, and often the success or failure may only become apparent during clinical trials. One of the problems associated with prediction of absorption from a typical 8-to 24-h MR dosage form is that, unlike for immediate release (IR) forms, the drug is released throughout the GI tract with a significant proportion delivered to the distal intestine. As a result, regional differences and, in particular, the efficiency of colonic absorption will be a critical consideration. For a variety of reasons, drug absorption in the colon appears to be more challenging than absorption in the proximal bowel. In physical terms, the colon is a viscous, low-mixing environment with a lower surface area for absorption compared with the proximal bowel. Both paracellular and transcellular permeabilities appear to be lower in th...

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Section: Discussionmentioning

confidence: 98%

Investigation of Regional Mechanisms Responsible for Poor Oral Absorption in Humans of a Modified Release Preparation of the α-Adrenoreceptor Antagonist, 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003): The Rational Use of ex Vivo Intestine to Predict in Vivo Absorption

Collett¹,

Stephens²,

Harwood³

et al. 2007

Drug Metab Dispos

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“…In fact, a 10,000 nmol/g oral dose was omitted from our initial study design because of GlySar precipitating out of the aqueous solution. Masaoka et al (2006) reported that, for poorly soluble compounds, concentrations in the small intestine could be 2-to 5-fold greater than anticipated because of rapid water absorption in the jejunum. Moreover, it is very unlikely that PEPT1 saturation alone was responsible for the reduction in dose-corrected AUC values because similar results were found in Pept1 knockout mice.…”

Section: In Vivo Oral Absorption and Disposition Of Glycylsarcosinementioning

confidence: 99%

“…Among these factors, permeability through the membrane, luminal drug concentration, and residence time are considered to be the most important factors for oral drug absorption (Kimura and Higaki, 2002;Masaoka et al, 2006). Luminal drug concentrations may change after oral administration because of intestinal absorption and by changes in fluid volume in each intestinal segment.…”

Section: In Vivo Oral Absorption and Disposition Of Glycylsarcosinementioning

confidence: 99%

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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“…Compared with stomach and small intestine, colon is boasted of low intensity and activity of digestive enzymes and neutral pH value, which enable proteins and peptides not to be hydrolyzed and degraded (Varum et al, 2008). Besides, the apical cell membrane in colon exhibits a greater degree of fluidity in comparison with that in small intestine, accounting for its high responsiveness to permeation enhancers (Masaoka et al, 2006;Philip & Philip, 2010). Moreover, colon may be more appropriate to be developed into a bioadhesive system than stomach and small intestine are, due to a thicker mucus layer and more moderate colonic motility (Varum et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Modified nanoparticles with cell-penetrating peptide and amphipathic chitosan derivative for enhanced oral colon absorption of insulin: preparation and evaluation

et al. 2015

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(2016) Modified nanoparticles with cell-penetrating peptide and amphipathic chitosan derivative for enhanced oral colon absorption of insulin: preparation and evaluation, Drug Delivery, 23:6, 2003-2014, DOI: 10.3109/10717544.2015 AbstractColon is an ideal absorptive site for oral protein and peptide drug (insulin), and yet it poses multiple barriers against the drug absorption, such as the barriers against the drug diffusion from colon lumen toward the absorptive mucosa and permeation across colon epithelium. In this study, modified nanoparticles (Tat-CS-NPs) with cell-penetrating peptide (Tat) and amphipathic chitosan derivative (a-CS) were used as carriers to improve colonic absorption of the drug. With a-CS as emulsifier and poly(lactic-co-glycolic acid) as matrix material, Tat-CS-NPs were prepared and evaluated in vitro/vivo. Using Caco-2 cell monolayers to imitate the colonic epithelial cells, it was found that the cellular uptake amount and transcellular transportation performance of Tat-CS-NPs were much enhanced compared with those of CS-NPs and PVA-NPs. The efficacy evaluation on diabetic rat models demonstrated that the hypoglycemic effect of Tat-CS-NPs loaded with insulin was 6.89 times higher than that of PVANPs, and 1.79 times higher than that of CS-NPs. By gavage of [ 99m Tc] isotope labeled Tat-CS-NPs in mini-pigs and single-photon emission computed tomography (SPECT) on pigs' gastrointestinal tract, it was further proved that the nanoparticles could reach colon and produce pharmacological effect. In conclusion, Tat-CS-NPs as vehicles for colon-specific drug delivery may be an efficient approach to improve oral bioavailability of protein and peptide drugs.

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Site of drug absorption after oral administration: Assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract

Cited by 153 publications

References 32 publications

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

Modified nanoparticles with cell-penetrating peptide and amphipathic chitosan derivative for enhanced oral colon absorption of insulin: preparation and evaluation

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