Effect of Loperamide on Na+/<scp>d</scp>-Glucose Cotransporter Activity in Mouse Small Intestine

Klaren, Peter H.M.; Giesberts, A N; Chapman, JC; White, S. J.; Taylor, C J; Hardcastle, P T; Hardcastle, J

doi:10.1211/0022357001774354

Cited by 10 publications

(7 citation statements)

References 28 publications

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“…Chelation techniques disrupting the enterocyte‐basement membrane interactions are a common method to isolate enterocytes from the underlying mucosal tissue to provide a relatively uncontaminated sample for membrane extraction . Alternatively, a mucosal scraping technique is applied to provide a yield of enterocytes where histological examination could be used to confirm the acquisition of villi . However, it is possible that other cell types potentially expressing the target proteins, i.e.…”

Section: Pbpk‐ivive Linked Models Of Intestinal Transportersmentioning

confidence: 99%

Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro–in vivo extrapolation of oral drug absorption

Harwood

Neuhoff

Carlson

et al. 2012

Biopharm & Drug Disp

101

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The use of whole body physiological-based pharmacokinetic (PBPK) models linked with in vitro-in vivo extrapolation (IVIVE) of kinetic parameters from laboratory experiments, has become embedded within many of the pharmaceutical industry and is used even as part of regulatory submissions. These include the influence of transporter proteins on drug disposition, a subject for which we have witnessed an increasing awareness. A combination of the development of high-powered analytical techniques and antibody-based technology, together with a realization that an understanding of absolute transporter protein abundances together with activity can potentially enhance the modelling of transporter kinetics by PBPK-IVIVE link models. This review summarizes the mechanistic approaches to integrate suitable non-biased in vitro transporter kinetic data relevant to the intestine (i.e. 'intrinsic' K i , 'intrinsic' K m ), by in vitro system modelling for these kinetic inputs with the advantages of, and challenges for, generating these data for input into PBPK models. This step is considered as a prerequisite for mechanistic modelling of the oral absorption for drugs that are substrates for transporters. Various approaches are provided to integrate intestinal transporter expression into PBPK models with a perspective on the incorporation of the absolute abundance/activity of transporters to enhance the predictive power of the models. We define the key intestinal tissue and functional expression-based scaling factors required. The objective is to use these for facilitating the extrapolation from in vitro intestinal transporter assays to the in vivo system, using absolute quantification methodologies. The models could be used to elucidate the complex relationship and relative importance of metabolizing enzymes and transporters in drug disposition and toxicity.

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Section: Pbpk‐ivive Linked Models Of Intestinal Transportersmentioning

confidence: 99%

Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro–in vivo extrapolation of oral drug absorption

Harwood

Neuhoff

Carlson

et al. 2012

Biopharm & Drug Disp

101

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“…In mouse small intestine, loperamide inhibited the glucose transporter by a calmodulin-independent mechanism [Klaren et al, 1999].…”

Section: Discussionmentioning

confidence: 99%

Further studies on the interaction of loperamide with capacitative calcium entry in Leukemic HL‐60 cells

Daly

Camerini-Otero

Shapiro

et al. 2006

Drug Development Research

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Loperamide at 3–10 µM has augmentative effects on calcium levels elevated by capacitative calcium entry (CCE) in leukemic HL‐60 cells after release of intracellular calcium by ATP or thapsigargin (Harper et al. [1997] Proc Natl Acad Sci USA 94:14912–14917). The effect of loperamide on calcium levels was absent at a pH value of 6.8, a pH at which CCE is not active in HL‐60 cells. Further investigations of HL‐60 cells in recent years revealed a great reduction in the magnitude of the loperamide response. However, when preceded by a CCE blocker, namely N‐methylnitrendipine (MRS 1844) or N‐propargylnitrendipine (MRS 1845), loperamide caused a significant reversal of the blockade. Six structural analogs of loperamide were synthesized, but only two showed loperamide‐like activity. Drug Dev. Res. 67:842–851, 2006. Published 2007 Wiley‐Liss, Inc.

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“…Brush-border membrane vesicles (BBMVs) were isolated from Swiss and transgenic CF (Cftr tm1Eur ) mice using a magnesium precipitation technique as described in detail by Klaren et al (2000). The proximal 75% intestine, measured from the ligament of Treitz, was removed, flushed with ice-cold saline (150 mM NaCl and 20 mM HEPES/ Tris, pH 7.4), cut open lengthwise and the mucosa scraped off with a microscope slide.…”

Section: Measurement Of Na + -Dependent Glucose Uptake By Brush-bordementioning

confidence: 99%

Small intestinal glucose absorption in cystic fibrosis: a study in human and transgenic ΔF508 cystic fibrosis mouse tissues

Hardcastle

Harwood

Taylor

2004

Journal of Pharmacy and Pharmacology

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Intestinal transport is disturbed in cystic fibrosis (CF), with both defective Cl- secretion and changes in absorption being reported. We have examined the effects of the disease on Na(+)-dependent glucose absorption by the small intestine. Active glucose absorption was monitored as changes in short-circuit current (SCC) in intact and stripped intestinal sheets from normal (Swiss) and transgenic CF (Cftr(tm1Eur) and Cftr(tm2Cam)) mice with the DeltaF508 mutation, and in jejunal biopsies from children with CF and normal controls. Na(+)-dependent glucose uptake at the luminal membrane was measured in brush-border membrane vesicles (BBMVs). Intact and stripped sheets of jejunum and midintestine from Swiss mice exhibited a concentration-dependent increase in SCC with glucose. Apparent Km values were similar in the two preparations, but the apparent Vmax was greater in stripped sheets. This difference was not due to a loss of neural activity in stripped sheets as tetrodotoxin did not influence the glucose-induced SCC in intact sheets. Similar results were observed in stripped sheets of jejunum and mid-intestine from wild-type Cftr(tm1Eur) mice, but in tissues from CF mice the apparent Vmax value was reduced significantly. A lower Vmax was also obtained in intact sheets of mid-intestine from CF (Cftr(tm2Cam)) mice. Jejunal biopsies from CF patients however, exhibited an enhanced glucose-dependent rise in SCC. Na(+)-dependent uptake by BBMVs from CF (Cftr(tm1Eur)) mice was not reduced compared with wild-type and Swiss BBMVs. It was concluded that, in contrast to human intestine, intestinal glucose absorption was reduced in transgenic mouse models of CF with the DeltaF508 mutation, but that this could not be detected in an isolated preparation of brush-border membranes. Transgenic mouse models of CF may not accurately reflect all aspects of intestinal dysfunction in the human disease.

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Effect of Loperamide on Na+/d-Glucose Cotransporter Activity in Mouse Small Intestine

Cited by 10 publications

References 28 publications

Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro–in vivo extrapolation of oral drug absorption

Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro–in vivo extrapolation of oral drug absorption

Further studies on the interaction of loperamide with capacitative calcium entry in Leukemic HL‐60 cells

Small intestinal glucose absorption in cystic fibrosis: a study in human and transgenic ΔF508 cystic fibrosis mouse tissues

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