Bosentan

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Bosentan
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Executive Summary Information

Compound Bosentan
Toxicities Cholestasis
Mechanisms Competitive inhibition of the BSEP bile salt export pump. Toxicity is attributed to the parent drug, and there is no evidence for formation of reactive metabolites.
Comments Bosentan is selected to exemplify induction of cholestasis without accompanying chemical reactivity or other promiscuous activity.
Feedback Contact Gold Compound Working Group (GCWG)
Bosentan
Bosentan.png
Identifiers
Leadscope Id LS-31532
CAS 147536-97-8
DrugBank DB00559
ChemSpider 94651
UNII XUL93R30K2
ChEBI 51450
Pathway DBs
KEGG D01227
Assay DBs
PubChem CID 104865
ChEMBL 957
Omics DBs
Properties
ToxCast Accepted no
Toxic Effect Cholestasis
ToxBank Accepted yes
Approved on 2012-01-01
Target endothelin receptor antagonist
Toxicities Cholestasis


In Vivo Data ? Compound Assessment
Adverse Events ? Hepatic adverse events

In clinical studies bosentan caused at least 3-fold upper limit of normal elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of cases.

References:

-Fattinger K et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001 69:223-31.

Non-hepatic adverse events
Based on animal data, bosentan is likely to cause major birth defects if used during pregnancy. Exclude pregnancy before and during treatment. In an open-label study (N=25), a decline in sperm count of at least 50% in 25% of bosentan-treated patients was observed after 3 or 6 months. Sperm count remained in normal range after 6 months, with no changes in sperm morphology, sperm motility, or hormone levels.

References:

- Tracleer (bosentan) full prescribing information. Actelion Pharmaceuticals US, Inc. February 2011

Toxicity Mechanisms ? Bosentan-induced liver injury can be explained by inhibition of BSEP, causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. Bosentan induces functional cholestasis and competes in a concentration-dependent fashion with bile salt elimination through liver canalicular membranes by inhibiting the bile salt export pump (BSEP). The inhibition of bile salt elimination by bosentan results in a concentration-dependent accumulation of bile salts, which are cytotoxic to hepatocytes at high concentrations.

References:

- Fattinger K et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001 Apr;69(4):223-31.

Concentration dependent competition with the biliary elimination of the bile salts, resulting in a retention of bile salts and a secondary increase in plasma aminotransferases. There is no evidence for the formation of a reactive metabolite, an immuno-allergic mechanism, mitochondrial toxicity or direct toxicity. Teratogenicity is thought to be a class effect for endothelin antagonists based on studies of knockout mice.

References:

-FDA cardiovascular and renal drugs advisory committee August 10 2001, briefing document concerning bosentan.

Serum bile salt levels in patients positively correlated with the bosentan dose and as the serum liver parameters after stopping of bosentan spontaneous normalized, it can be concluded that bosentan acts as a competitive BSEP inhibitor. This inhibition of BSEP seems to be rather specific, as no elevation of serum bilirubin was observed. Most interestingly, in a follow-up investigation of the cholestatic mechanism of bosentan in rats it was found that, contrary to the expectations bosentan leads to a stimulation of bile flow. The increased bile flow was not caused by an increased bile salt output, but was associated with an increased glutathione and bicarbonate secretion. This stimulation of bile flow was not observed in TR− rats, which lack functional Mrp2. Hence, bosentan not only directly affects the function of Bsep as a competitive inhibitor, but also exerts indirect effects, which depend on Mrp2. In vitro characterization of rat and human MRP2 as well as BSEP expressed in Sf9 cells confirmed the inhibition by bosentan of both isoforms of Bsep/BSEP. Furthermore, this study demonstrated a direct stimulation of Mrp2/MRP2 transport activity by bosentan. This finding most likely presents the molecular explanation for the observed increase of bile salt-independent bile flow in rats

References:

- http://www.medscape.com/viewarticle/724143_7

Therapeutic Target ? Bosentan is a dual ETA and ETB endothelin receptor antagonist and is used to treat pulmonary hypertension by blocking the action of endothelin molecules Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension.

ET is a potent growth factor in combination with other growth factors such as platelet-derived growth factor. Bosentan inhibits the growth-inducing effects of ET; bosentan significantly reduces vascular hypertrophy, neointima formation and cardiac hypertrophy. ET also stimulates collagen synthesis. This fibrotic effect is essentially mediated via ETB receptors.

References:

- http://www.drugbank.ca/drugs/DB00559
-EMEA 2005: WC500041457

FDA and Label Information

The following link will display all of the currently approved FDA drug products on the market. The web page will contain a table listing all current products by their respective Tradenames and primary active ingredients. The list is navigable by simply clicking on the product of interest, which will in turn list all of the NDA's and ANDA's associated with that product. From here users can click on a specific NDA or ANDA and see documents that have been submitted for the product that the FDA has made available via their website. The types of documents include approval history, letters, reviews and labels.
FDA Approved Products

This next url will perform a search in the FDA's system for all labels for products that contain Bosentan as an active ingredient.
FDA Label Search

Since every unique drug product receives a separate label, we have included a link to another resource for a specific Acetaminophen product (ACETAMINOPHEN liquid - by Goldline Laboratories, Inc.) which displays the drug label information.
Bosentan tablets label

PubMed references

The following resource link will perform a PubMed query for the terms "bosentan" and "liver toxicity".
Bosentan Search

PK-ADME ? Compound Assessment
PK parameters ? Bioavailability = 50%

Vd = 18 L (0.25 L/kg) Tmax = 3.5 h to peak plasma concentration, steady state levels are achieved within 3-5 days T1/2 = 5 h. Cmax (mg/l): mean 3.724 (following a single oral dose of 500 mg) Protein binding: > 98% to plasma proteins, mainly albumin. Eliminated by hepatic metabolism (CYP2C9, CYP3A4) and subsequent biliary excretion of the metabolites

References:

-http://www.drugbank.ca/drugs/DB00559
-EMEA 2005: WC500041457
-FDA cardiovascular and renal drugs advisory committee August 10 2001, briefing document concerning bosentan
-C. Weber et al ., Absorption, Excretion, and Metabolism of the Endothelin Receptor Antagonist Bosentan in Healthy Male Subjects, Drug Metabolism and Disposition DMD July 1, 1999 vol. 27 no. 7 810-815

Successful modeling of in vivo PK in humans based on data for uptake and metabolism in sandwich cultures of hepatocytes has been demonstrated for a series of transporter modulators but required empirical scaling factors and was less predictive for bosentan than for other modulators in the series.

References:

-Hannah M. Jones, Hugh A. Barton, Yurong Lai, Yi-an Bi, Emi Kimoto, Sarah Kempshall, Sonya C. Tate, Ayman El-Kattan, J. Brian Houston, Aleksandra Galetin, and Katherine S. Fenner (2012) “Mechanistic Pharmacokinetic Modeling for the Prediction of Transporter-Mediated Disposition in Humans from Sandwich Culture Human Hepatocyte Data”, Drug Metab Disp 40:1007-1017.
Therapeutic window ? Bosentan treatment is initiated at a dose of 62.5 mg bid for 4 weeks and then increased to the maintenance dose of 125 mg twice daily. Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support

References:

-http://www.drugbank.ca/drugs/DB00559

At the recommended maximum dose of 125 mg bid (3 umol/kg), Cmax = 930 ug/L (1.7 uM). Increased exposure to the liver via the portal vein can be assumed to reach ~17 uM, comparable to the IC50 for BSEP.

Metabolically activated ? Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound

References:

-http://www.drugbank.ca/drugs/DB00559

Metabolic activation: There is no evidence for the formation of a reactive metabolite.

References:

- FDA cardiovascular and renal drugs advisory committee August 10 2001, briefing document concerning bosentan.

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? J. Weiss et al. Differential modulation of the expression of important drug metabolising enzymes and transporters by endothelin-1 receptor antagonists ambrisentan and bosentan in vitro.

References:

-European Journal of Pharmacology Volume 660, Issues 2-3, 25 June 2011, Pages 298-304


Lim KA, Kim KC, Cho MS, Lee BE, Kim HS, Gene expression of endothelin-1 and endothelin receptor a on monocrotaline-induced pulmonary hypertension in rats after bosentan treatment.

References:

-Korean Circ J. 2010 Sep;40(9):459-64.


Brit Fitzner et al. Synergistic growth inhibitory effects of the dual endothelin-1 receptor antagonist bosentan on pancreatic stellate and cancer cells

References:

-Dig Dis Sci. 2009 Feb; 54(2):309-20.

Proteomics profiles known. ?
Metabonomics profiles known. ?
Fluxomics profiles known. ?
Epigenomics profiles known. ?
Observed IC50 for in vitro cellular efficacy. ? Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB with a slightly higher affinity for ETA receptors (Ki = 4.1– 43 nM) than for ETB receptors (Ki = 38-730 nM).
Observed IC50 for in vitro cellular toxicity studies. ? Membrane vesicles derived from Spodoptera frugiperda (Sf) 9 cells: The adenosine 5'-triphosphate (ATP)-dependent uptake of (3)H-taurocholic acid into membrane vesicles for BSEP/Bsep was inhibited by bosentan, and its IC50 values were 77 and 100 microM for human BSEP and rat Bsep

References:

-Mano Y, et al. "Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance-associated protein 2.", Biopharm Drug Dispos. 2007; 28(1):13-18.


IC50 vs human BSEP = 22 uM.

References:

- Ryan E. Morgan, et al., "Interference with Bile Salt Export Pump Function Is a Susceptibility Factor for Human Liver Injury in Drug Development". TOXICOLOGICAL SCIENCES 118(2), 485–500 (2010).


Bosentan was a more potent inhibitor of taurocholate uptake into hepatocytes by rat Na+-dependent taurocholate co-transporting polypeptide (Ntcp/Slc10a1) (IC50 0.71 microM) than human NTCP (SLC10A1) (IC50 24 microM) expressed in HEK293 cells. The result is that, for rats, bosentan causes increases in bile salts in the circulation but not in hepatocytes.

References:

- E. M. Leslie et al. "Differential Inhibition of Rat and Human Na_-Dependent Taurocholate Cotransporting Polypeptide (NTCP/SLC10A1) by Bosentan: A Mechanism for Species Differences in Hepatotoxicity," JPET (2007) Vol. 321, No. 3

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? No - Not included in ToxCast Phase I and II Chemicals List.

soluble in DMSO (−1 < log P < 6, i.e., log of the octanol/water partition coefficient; 97.5% meet this criteria) Log P experimental 3.7 meets criteria [www.drugbank.ca/drugs/DB00559, accessed September 5, 2011] molecular weight range 250–1000 (90% meet this criteria) Bosentan 551.6 g/mol meets criteria

Substance stability. ? The stability of bosentan has been examined under a variety of stress testing conditions. Real-time and accelerated stability studies have been performed on bosentan powder in accordance with the ICH Guideline. No significant changes in any parameter were observed. The proposed retest period of 3 years (and no special storage conditions) is justified.

References:

- Tracleer, INN-Bosentan, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000401/WC500041457.pdf

Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Poorly soluble in water (1.0 mg/100 ml) and in aqueous solutions at low pH (0.1 mg/100 ml at pH 1.1 and 4.0; 0.2 mg/100 ml at pH 5.0). Solubility increases at higher pH values (43 mg/100 ml at pH 7.5).

References:

- www.drugbank.ca/drugs/DB00559

estimated intrinsic solubility : 4.2428E-2 mg/ml estimated solubility in pure water at pH 5.04: 4.7391E-2mg/ml estimated solubility in water at pH 7.4: 0.94 mg/ml Calculations performed using ACD/PhysChem v 9.14

Solubility in DMSO 100 times buffer solubility. ? Soluble

References:

- http://www.usbio.net/item/B2573?highlight

Vessel binding properties. ?
Vapor pressure. (Non-volatile) ? estimated vapor pressure: 1.9E-19 mmHg (Calculation performed using EPI Suite v4.10)

Authors of this ToxBank wiki page

David Bower, Egon Willighagen
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