Abstract
The combinations of the endothelin-1 receptor antagonists bosentan or ambrisentan with the phosphodiesterase 5 inhibitors sildenafil or tadalafil are current standard therapies of advanced pulmonary arterial hypertension. However, these drugs have a number of drug interactions. Changes of bosentan pharmacokinetics by sildenafil are attributed to reduced hepatic uptake as a consequence of inhibition of organic anion transporting polypeptides. We therefore tested in vitro the hypothesis that sildenafil and tadalafil reduce the enzyme- and transporter-inducing effects of bosentan or ambrisentan by preventing cellular access. Although intracellular concentrations of bosentan and ambrisentan (measured by high pressure liquid chromatography coupled with tandem mass-spectrometry) after four days of incubation of LS180 cells were lower when sildenafil or tadalafil were present, quantification of mRNA expression in these cells by real-time reverse transcription polymerase chain reaction revealed that bosentan and ambrisentan-mediated induction was stable or even increased in combination with sildenafil or tadalafil. For the drug transporter P-glycoprotein this was confirmed at the protein and functional level with highly significant correlations between P-gp mRNA, protein, and function. Moreover, using a reporter gene assay in LS180 cells, our study demonstrates for the first time that tadalafil is a potent, ambrisentan a weak, and sildenafil no activator of pregnane X receptor. In conclusion, our study demonstrates that although sildenafil and tadalafil indeed reduce intracellular concentrations of bosentan and ambrisentan in LS180 cells, they do not mitigate the inducing effects of these endothelin-1 receptor antagonists.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
-
Antihypertensive Agents / analysis
-
Antihypertensive Agents / metabolism
-
Antihypertensive Agents / pharmacology
-
Biological Transport
-
Bosentan
-
Carbolines / adverse effects
-
Carbolines / pharmacology*
-
Cell Line, Tumor
-
Cytochrome P-450 CYP3A / genetics
-
Cytochrome P-450 CYP3A / metabolism
-
Drug Interactions
-
Endothelin A Receptor Antagonists*
-
Gene Expression Regulation / drug effects
-
Genes, Reporter / drug effects
-
Humans
-
Intestinal Absorption / drug effects
-
Intestinal Mucosa / metabolism
-
Intestines / drug effects*
-
Intestines / enzymology
-
Peroxisome-Targeting Signal 1 Receptor
-
Phenylpropionates / analysis
-
Phenylpropionates / metabolism
-
Phenylpropionates / pharmacology*
-
Phosphodiesterase 5 Inhibitors / pharmacology*
-
Piperazines / adverse effects
-
Piperazines / pharmacology*
-
Pregnane X Receptor
-
Promoter Regions, Genetic / drug effects
-
Purines / adverse effects
-
Purines / pharmacology
-
Pyridazines / analysis
-
Pyridazines / metabolism
-
Pyridazines / pharmacology*
-
RNA, Messenger / metabolism
-
Receptors, Cytoplasmic and Nuclear / genetics
-
Receptors, Cytoplasmic and Nuclear / metabolism
-
Receptors, Steroid / genetics
-
Receptors, Steroid / metabolism
-
Recombinant Proteins / metabolism
-
Sildenafil Citrate
-
Sulfonamides / analysis
-
Sulfonamides / metabolism
-
Sulfonamides / pharmacology*
-
Sulfones / adverse effects
-
Sulfones / pharmacology*
-
Tadalafil
Substances
-
ABCB1 protein, human
-
ATP Binding Cassette Transporter, Subfamily B
-
ATP Binding Cassette Transporter, Subfamily B, Member 1
-
Antihypertensive Agents
-
Carbolines
-
Endothelin A Receptor Antagonists
-
Peroxisome-Targeting Signal 1 Receptor
-
Phenylpropionates
-
Phosphodiesterase 5 Inhibitors
-
Piperazines
-
Pregnane X Receptor
-
Purines
-
Pyridazines
-
RNA, Messenger
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Steroid
-
Recombinant Proteins
-
Sulfonamides
-
Sulfones
-
Tadalafil
-
Sildenafil Citrate
-
Cytochrome P-450 CYP3A
-
CYP3A4 protein, human
-
ambrisentan
-
Bosentan