Dipeptide Transport in the Intestinal Mucosa of Developing Rabbits

Rubino, A; Guandalini, Stefano

doi:10.1002/9780470720318.ch5

Cited by 9 publications

(1 citation statement)

References 32 publications

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“…Indeed, functional studies in rabbits and guinea pigs confirm that the rate and extent of dipeptide transport is greatest in suckling newborns compared with weaning or adult animals. [22,23] Although the ontogeny of PEPT1 has not been characterized in humans, data derived from lower mammals are consistent with the functional studies and suggest the early postnatal expression of PepT1. In rats, PepT1 messenger RNA (mRNA) expression increases rapidly at birth and is highest in all segments of the small intestine by 3-5 days of life.…”

Section: Absorptionsupporting

confidence: 75%

Pharmacologic Considerations for Oseltamivir Disposition

2011

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Across much of the world, pandemic H1N1 infection has produced a significant healthcare crisis, reflected in significant morbidity and mortality. Statistics reveal that infection-associated deaths among individuals without pre-existing conditions (e.g. immunosuppression) are clustered in pregnant women and young infants. In developing countries where the availability of influenzae vaccine is limited, the only currently available pharmacologic counter-measure for H1N1 disease is oseltamivir, a neuraminidase inhibitor with excellent in vitro activity against the virus. This drug is available in oral solid and liquid formulations, has excellent peroral bioavailability in adults, and generally has a very favorable safety profile. Many observational studies indicate that oseltamivir treatment is associated with symptomatic improvement in pediatric patients with H1N1 infection and, therefore, is considered to represent a viable therapeutic option for use in children. However, the disposition of the ethyl ester prodrug and its active metabolite has not been well characterized in infants and children. Presently, data are available from only two published investigations and preliminary summary information from a recent presentation of an ongoing study. Given that recent in vitro data support the importance of a target exposure-response profile for the active metabolite of oseltamivir and that many processes known to modulate drug disposition have a developmental basis, understanding the potential impact of age on oseltamivir disposition becomes crucial in the development of age-appropriate dosing regimens for the drug. In this review, the impact of ontogeny on processes that are important in regulating the absorption, distribution, metabolism, and excretion of oseltamivir and its active metabolite are considered. Data from both animal and human investigations are presented in the context of defining how development might influence the dose-exposure relationship and, most importantly, the significant variability associated with it. In addition, the available pediatric pharmacokinetic data for oseltamivir and its active metabolite are summarized and current 'information gaps' deserving of future study are presented.

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Section: Absorptionsupporting

confidence: 75%

Pharmacologic Considerations for Oseltamivir Disposition

2011

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Untersuchungen zur Spontansolubilisierung mucosaler Peptidhydrolasen des Dünndarms der Ratte

Mooz

Friedrich

Noack

1979

Nahrung

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In vitro incubations of small intestine preparation lead to the spontaneous release of mucosal enzymes into the incubation medium, due to superficial dissolution and membrane lesions. One-hour anaerobic incubation of everted small intestine segments produces the liberation of from 13% (leucine arylamidase) to 30% (Gly-L-Pro-splitting peptide hydrolase) of the mucosal enzyme activities. Under the conditions of in vivo perfusion, the solubilization rates are from 50 to 80% lower than these values. The tendency to solubilization is only in part reduced to a significant extent by the saturation of the incubation medium with oxygen, but it does not reach the in vivo level. The detectability of membrane-bound and intracellular marker enzymes in the incubation medium permits no conclusions concerning the physiological localization of the released peptidases.

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H+/Di-tripeptide transporter (PepT1) expression in the rabbit intestine

et al. 1995

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In order to examine the intestinal expression of the recently cloned H+/di-tripeptide transporter (PepT1), oligonucleotide probes were synthesized and their specificity confirmed by Northern blot analysis of rabbit jejunal RNA. In situ hybridization studies, using these probes, show that PepT1 is expressed all along the small intestine and at a very much reduced level in the colon. In contrast, PepT1 mRNA was not detected in the stomach, sacculus rotundus or caecum. Microscopic examination of tissue sections showed PepT1 expression to be restricted to intestinal epithelium with no detectable expression in the lamina propria, muscularis mucosae, muscularis or serosa. The accumulation of PepT1 mRNA along the crypt-villus axis was also investigated. In all regions of the small intestine (in duodenum, jejunum and ileum), PepT1 mRNA was undetectable in deeper epithelial cells of the crypts. Expression was first detectable at or near the crypt-villus junction, the amount of PepT1 mRNA increasing rapidly in the lower villus to a maximum approximately 100-200 microns from this point. Along the length of the small intestine PepT1 mRNA was most abundant in duodenal and jejunal enterocytes, with lower levels in the ileal epithelium. PepT1 expression is greatly depressed in the follicle-associated epithelium of the Peyer's patch relative to both interfollicular and adjacent "normal" villi. These data are discussed in the context of the known physiological role of PepT1 in the gastrointestinal tract.

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Dipeptide Transport in the Intestinal Mucosa of Developing Rabbits

Cited by 9 publications

References 32 publications

Pharmacologic Considerations for Oseltamivir Disposition

Pharmacologic Considerations for Oseltamivir Disposition

Untersuchungen zur Spontansolubilisierung mucosaler Peptidhydrolasen des Dünndarms der Ratte

H+/Di-tripeptide transporter (PepT1) expression in the rabbit intestine

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