Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When propafenone is given with digoxin, digoxin serum concentrations increase. Although the digoxin-propafenone interaction is well known clinically, the mechanism by which propafenone interferes with digoxin elimination is unclear. To test the hypothesis that propafenone or one or both of its two major metabolites, 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP), inhibit the P-glycoprotein-mediated net renal tubular secretion of digoxin, we examined the transport of digoxin and the well-studied P-glycoprotein substrate vinblastine across confluent Madin-Darby canine kidney cell monolayers in the absence and presence of propafenone, 5-OHP and NDPP. Propafenone and its two major metabolites significantly inhibit the secretory flux of digoxin and vinblastine (propafenone > 5-OHP >> NDPP). Despite decreases in net transport, cellular digoxin accumulation did not decrease, suggesting that neither propafenone nor its metabolites prohibited digoxin from entering the cells at the basolateral side. NDPP, but not 5-OHP, was detected after 48 hr of incubation of the cells with propafenone alone. When the cells were incubated with propafenone or 5-OHP, apical accumulation of 5-OHP, but neither propafenone nor NDPP, against a concentration gradient was observed. These findings are consistent with the hypothesis that the digoxin-propafenone interaction results from the inhibition of the renal tubular transport of digoxin by propafenone and its metabolites. Our data suggest that propafenone is an inhibitor of P-glycoprotein, whereas 5-OHP is a possible substrate.
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PMID:The digoxin-propafenone interaction: characterization of a mechanism using renal tubular cell monolayers. 933 6

The presence of a nitrogen atom, charged at physiological pH, has frequently been considered to be a hallmark of P-glycoprotein (PGP) inhibitors, although certain steroids, such as progesterone, lack a nitrogen atom and still are active modulators of PGP. The present study was aimed at investigating the role the nitrogen atom plays in the activity of PGP inhibitors. Propafenone-related amines, anilines, and amides that cover a broad range of pK(a) values, as well as an ester, were synthesized and tested for multidrug resistance-reverting activity. The sum of the hydrogen bond acceptor strengths was calculated and correlated with EC(50) values for PGP inhibition. For the complete set of 12 compounds, an excellent correlation between these two parameters was found; this included the ester GP570, which lacks a nitrogen atom but contains the strong hydrogen bond-accepting ester unit. The interaction of the nitrogen atom with PGP therefore is nonional and is determined by the sum of the hydrogen acceptor strengths of the region. The high predictivity of the obtained model is demonstrated in a leave-one-out cross-validation procedure.
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PMID:The importance of a nitrogen atom in modulators of multidrug resistance. 1049 63

Propafenone analogs (PAs) were previously identified as potent inhibitors of P-glycoprotein (Pgp)-mediated toxin efflux. For this as well as other classes of Pgp inhibitors, lipophilicity as well as hydrogen bond acceptor strength are important determinants of biological activity. The question as to whether a direct interaction between PA-type modulators and Pgp takes place was addressed by means of Pgp ATPase measurements and transport studies. Propafenone-type modulators stimulated ATPase activity up to 2-fold over basal activity in a concentration-dependent biphasic manner. Within a series of structural homologs, Ka values of ATPase stimulation strongly correlated with lipophilicity. Analogs containing a quaternary nitrogen stimulated Pgp ATPase activity with lesser efficacy, while Ka values were somewhat higher when compared to corresponding tertiary analogs. Transport studies performed in inside-out plasma membrane (I/O) vesicles demonstrated that analogs containing a tertiary nitrogen rapidly associated with the biomembrane. Quaternary analogs, which are restricted by a permanent positive charge in transiting the plasma membrane by diffusion, accumulated in Pgp containing I/O vesicles in an ATP-dependent and cyclosporin A-inhibitable manner, which identified them as Pgp substrates. Identical structure-activity relationships were found in either Pgp ATPase stimulation experiments in I/O vesicles or in toxin efflux inhibition studies using intact cells. Therefore, differences in membrane transit are not responsible for the observed structure-activity relationships.
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PMID:Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements. 1051 88

Multidrug resistance transporters P-glycoprotein/ABCB1 and ABCG2 limit the effect of a large number of cytostatic and cytotoxic drugs by energy-dependent efflux. In experimental models, pump inhibitors reestablish sensitivity towards these drugs. Both transporters demonstrate remarkably broad and partly overlapping substrate specificity. Propafenone analogues are inhibitors of a large number of drug efflux pumps including P-glycoprotein and ABCG2 as well as the microbial pumps. Here the two human ABC transporters ABCB1 and ABCG2 have been studied with respect to interaction with this class of compounds. Data indicate that within the same chemical scaffold, selectivity indices span three orders of magnitude. Compounds with the highest selectivity indices contain a non-ionizable nitrogen atom. Qualitative and quantitative pharmacophore models indicate that hydrophobicity, the number of rotatable bonds, and the number of H-bond acceptors are key features for both activity and selectivity.
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PMID:Multispecificity of drug transporters: probing inhibitor selectivity for the human drug efflux transporters ABCB1 and ABCG2. 1799 97