Skip to Content
MilliporeSigma

Macitentan does not interfere with hepatic bile salt transport.

The Journal of pharmacology and experimental therapeutics (2014-04-29)
Alexander Treiber, Päivi Äänismaa, Ruben de Kanter, Stephane Delahaye, Marianne Treher, Patrick Hess, Patricia Sidharta
ABSTRACT

Treatment of pulmonary arterial hypertension with the endothelin receptor antagonist bosentan has been associated with transient increases in liver transaminases. Mechanistically, bosentan inhibits the bile salt export pump (BSEP) leading to an intrahepatic accumulation of cytotoxic bile salts, which eventually results in hepatocellular damage. BSEP inhibition by bosentan is amplified by its accumulation in the liver as bosentan is a substrate of organic anion-transporting polypeptide (OATP) transport proteins. The novel endothelin receptor antagonist macitentan shows a superior liver safety profile. Introduction of the less acidic sulfamide moiety and increased lipophilicity yield a hepatic disposition profile different from other endothelin receptor antagonists. Passive diffusion rather than OATP-mediated uptake is the driving force for macitentan uptake into the liver. Interaction with the sodium taurocholate cotransporting polypeptide and BSEP transport proteins involved in hepatic bile salt homeostasis is therefore limited due to the low intrahepatic drug concentrations. Evidence for this conclusion is provided by in vitro experiments in drug transporter-expressing cell lines, acute and long-term studies in rats and dogs, absence of plasma bile salt changes in healthy human volunteers after multiple dosing, and finally the liver safety profile of macitentan in the completed phase III morbidity/mortality SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Methanol, anhydrous, 99.8%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Supelco
Methanol, analytical standard
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Cyclosporin A, 97.0-101.5% (on dried basis)
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, suitable for HPLC, gradient grade, 99.93%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Cyclosporin A, from Tolypocladium inflatum, ≥95% (HPLC), solid
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Rifampicin, suitable for plant cell culture, BioReagent, ≥95% (HPLC), powder or crystals
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Ethanol Fixative 80% v/v, suitable for fixing solution (blood films)
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Cyclosporin A, BioReagent, from Tolypocladium inflatum, for molecular biology, ≥95%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Rifampicin, ≥95% (HPLC), powder or crystals
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, SAJ special grade
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Supelco
Ethanol solution, certified reference material, 2000 μg/mL in methanol
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, suitable for HPLC
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, SAJ first grade, ≥99.5%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, JIS 300, ≥99.8%, for residue analysis
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Ethanol, JIS special grade, 94.8-95.8%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, JIS special grade, ≥99.8%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, NMR reference standard
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Supelco
Dehydrated Alcohol, Pharmaceutical Secondary Standard; Certified Reference Material
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Ethanol, JIS first grade, 94.8-95.8%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, HPLC Plus, ≥99.9%, poly-coated bottles
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Supelco
Cyclosporin A, VETRANAL®, analytical standard
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Ethyl alcohol, Pure 190 proof, for molecular biology
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
USP
Dehydrated Alcohol, United States Pharmacopeia (USP) Reference Standard
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Supelco
Methanol, Pharmaceutical Secondary Standard; Certified Reference Material
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, Absolute - Acetone free
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, ACS reagent, ≥99.8%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8% (GC)
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, ACS reagent, ≥99.8%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, puriss., meets analytical specification of Ph Eur, ≥99.7% (GC)
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75
Sigma-Aldrich
Methanol, BioReagent, ≥99.93%
Sign Into View Organizational & Contract Pricing
SKUPack SizeAvailabilityPriceQuantity
1 mg
In Stock
Details...
$285.00
$213.75