Cyclosporin metabolism by human gastrointestinal mucosal microsomes.

Webber, IR; Peters, Wilbert H.M.; Back, DJ

doi:10.1111/j.1365-2125.1992.tb04098.x

Cited by 40 publications

(10 citation statements)

References 19 publications

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“…Since just passive diffusion does not explain the decreased bioavailability after colonic administration, additional factors have to be considered for the absorption process. Besides the influence exerted by gastrointestinal juices such as bile (Venkatamaranan, 1985;Mehta et al, 1988), presystemic metabolism could also contribute to the variability in CyA absorption (Vickers et al, 1992;Webber et al, 1992). The previous finding of a higher CyA metabolism in duodenum as compared to colon (Webber et al, 1992) is not compatible with our results.…”

Section: Discussioncontrasting

confidence: 75%

Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation

Fricker¹,

Drewe

Huwyler

et al. 1996

British J Pharmacology

207

134

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. The interaction of cyclosporin A (CyA) with p‐glycoprotein during intestinal uptake was investigated by a combination of in vitro experiments with human Caco‐2 cells and an intubation study in healthy volunteers. . CyA uptake into the cells was not saturable and exhibited only a low temperature sensitivity, suggesting passive diffusion. When the permeation of CyA across Caco‐2 monolayers from the apical to the basolateral side was determined, overall transport had an apparently saturable component up to a concentration of 1 μm. At higher concentrations permeation increased over‐proportionally. Calculation of the kinetic parameters of apical to basolateral permeation suggested a diffusional process with a KD of 0.5 μl min−1 per filter, which was overlayed by an active system in basolateral to apical direction with a KM of 3.8 μm and a Jmax of 6.5 picomol min−1 per filter. . CyA permeation was significantly higher when the drug was given from the basolateral side as compared to the permeation from the apical side. Apical to basolateral transport of CyA was increased in the presence of vinblastine, daunomcyin and a non‐immunosuppressive CyA‐derivative. All compounds inhibit p‐glycoprotein‐mediated transport processes. Basolateral to apical permeation of CyA showed a dose‐dependent decrease in the presence of vinblastine. Permeation of daunomycin across Caco‐2 cell monolayers was also higher from the basolateral to the apical side than vice versa. Basolateral to apical permeation was decreased in the presence of SDZ PSC 833 and cyclosporin A. . Western blot analysis of Caco‐2 cells with the monoclonal antibody C219 confirmed the presence of p‐glycoprotein in the used cell system. . When the absorption of CyA in the gastrointestinal (G***I)‐tract of healthy volunteers was determined, a remarkable decrease of the plasma AUC could be observed dependent on the location of absorption in the rank order stomach > jejunum/ileum > colon. The decrease in absorption exhibited a marked correlation (r = 0.994) to the expression of mRNA for p‐glycoprotein over the G**I‐tract (stomach < jejunum < colon). . All data provide evidence that CyA is a substrate of p‐glycoprotein in the G***I‐tract, which might explain the local differences and the high variability in cyclosporin absorption found in vivo.

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Section: Discussioncontrasting

confidence: 75%

Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation

Fricker¹,

Drewe

Huwyler

et al. 1996

British J Pharmacology

207

134

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“…The design variables and their settings (high and low values in the design) were selected on the basis of variations in previously reported microsomal incubation conditions for CsA [14][15][16][17]. Both Tris-and phosphate buffers have previously been applied [16,17].…”

Section: Cyp3a4 Metabolism Of Csamentioning

confidence: 99%

“…1), and is one out of eight recommended CYP3A4 probes in current guidelines [4,5]. The variety of microsomal incubation conditions used in former studies on CYP3A4 metabolism of CsA was applied as limits for the statistical experimental design [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Microsomal Incubation Conditions on CYP3A4-Mediated Metabolism of Cyclosporine A by a Statistical Experimental Design

Hermann¹,

Kase²,

Molden³

et al. 2006

CDM

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The effect of changes in microsomal incubation conditions (NADPH, Mg(2+), Cl(-), NADPH-regenerating system and pH) on the formation of the CYP3A4 metabolites AM1 and AM9 from CsA were studied by application of a fractional factorial design. Metabolism was studied in microsomes of transfected human liver epithelial (THLE) cells specifically expressing CYP3A4. Within the conditions tested, a 3-4-fold difference in formation of CsA metabolites was observed. Formation of both AM1 and AM9 was favoured by a low Mg(2+) concentration (0.5 mM) and no addition of Cl(-) to the incubation matrix. However, while a high NADPH concentration (1.75 mM) was the single most important factor for the formation of AM1, changes in NADPH concentration between 0.25 and 1.75 mM had no influence on AM9 formation. Formation of the two metabolites also differed in their influence by pH changes, as a change in pH from 7.2 to 7.5 significantly increased the formation of AM9, while formation of AM1 was unaffected by this change. The present study showed that relatively small changes in the incubation matrix had a significant influence on the microsomal CYP3A4-mediated metabolism of CsA. Systematic studies on microsomal incubation conditions could be a key to improve metabolic in vitro-in vivo extrapolations in drug development.

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“…It was also noted that the plasma levels of paclitaxel obtained in wild-type mice cotreated with CsA were even higher than those obtained in knockout mice that were treated with oral paclitaxel without CsA. This can be explained by increased uptake by inhibition of P-gp in the gastrointestinal tract and decreased elimination by inhibition of CYP3A [104][105][106][107]. However, blockade of other yet unidentified drug transporters or drug eliminating pathways cannot be ruled out.…”

Section: Paclitaxelmentioning

confidence: 99%

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

2002

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The oral bioavailability of many cytotoxic drugs is low and/or highly variable. This can be caused by high affinity for drug transporters and activity of metabolic enzymes in the gastrointestinal tract and liver. In this review, we will describe the main involved drug transporters and metabolic enzymes and discuss novel methods to improve oral treatment of affected substrate drugs. Results of preclinical and clinical phase I and II studies will be discussed in which affected substrate drugs, such as paclitaxel, docetaxel, and topotecan, are given orally in combination with an inhibitor of drug transport or drug metabolism. Future randomized studies will, hopefully, confirm that this strategy for oral treatment is at least as equally effective and safe as standard intravenous administration of these drugs. The Oncologist 2002;7:516-530

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Cyclosporin metabolism by human gastrointestinal mucosal microsomes.

Cited by 40 publications

References 19 publications

Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation

Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation

Evaluation of Microsomal Incubation Conditions on CYP3A4-Mediated Metabolism of Cyclosporine A by a Statistical Experimental Design

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

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