Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84).

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Haslam IS, Jones K, Coleman T, Simmons NL

Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84).

Biochem Pharmacol. 2008 Oct 1;76(7):850-61. doi: 10.1016/j.bcp.2008.07.020. Epub 2008 Jul 23.

PubMed ID

18703021 [ View in PubMed

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Abstract

Intestinal induction of Pgp is known to limit the oral availability of certain drug compounds and give rise to detrimental drug-drug interactions. We have investigated the induction of P-glycoprotein (Pgp; MDR1) activity in a human intestinal epithelial cell line (T84) following pre-exposure to a panel of drug compounds, reported to be Pgp substrates, inhibitors or inducers. Human MDR1-transfected MDCKII epithelial monolayers were used to assess Pgp substrate interactions and inhibition of digoxin secretion by the selected drug compounds. The T84 cell line was used to assess induction of Pgp-mediated digoxin secretion following pre-exposure to the same compounds. Changes in gene expression (MDR1, MRP2, PXR and CAR) were determined by quantitative RT-PCR. Net transepithelial digoxin secretion was increased (1.3 fold, n=6, P<0.05) following pre-exposure to the PXR activator hyperforin (100nM, 72h), as was MDR1 mRNA expression (3.0 fold, n=4, P<0.05). A number of Pgp substrates (quinidine, amprenavir, irinotecan, topotecan, atorvastatin and erythromycin) induced net digoxin secretion, as did the non-Pgp substrate artemisinin. Various non-Pgp substrates demonstrated inhibition of digoxin secretion (verapamil, mifepristone, clotrimazole, mevastatin, diltiazem and isradipine) but did not induce Pgp-mediated digoxin secretion. Of the compounds that increased Pgp secretion, quinidine, topotecan, atorvastatin and amprenavir pre-exposure also elevated MDR1 mRNA levels, whereas erythromycin, irinotecan and artemisinin displayed no change in transcript levels. This indicates possible post-translational regulation of digoxin secretion. Finally, a strong correlation between drug modulation of MRP2 and PXR mRNA expression levels was evident.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Digoxin	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
Integrate drug-drug interactions in your software
Digoxin Levothyroxine	Levothyroxine may increase the excretion rate of Digoxin which could result in a lower serum level and potentially a reduction in efficacy.
Digoxin Prednisolone phosphate	Prednisolone phosphate may increase the excretion rate of Digoxin which could result in a lower serum level and potentially a reduction in efficacy.
Digoxin Dexamethasone acetate	Dexamethasone acetate may increase the excretion rate of Digoxin which could result in a lower serum level and potentially a reduction in efficacy.
Digoxin Lorlatinib	Lorlatinib may increase the excretion rate of Digoxin which could result in a lower serum level and potentially a reduction in efficacy.