Miljöpåverkan
Ambrisentan
Miljörisk:
Risk för miljöpåverkan av ambrisentan kan inte uteslutas då ekotoxikologiska data saknas.
Nedbrytning:
Det kan inte uteslutas att ambrisentan är persistent, då data saknas.
Bioackumulering:
Ambrisentan har låg potential att bioackumuleras.
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Detaljerad miljöinformation
Environmental Risk Classification
Predicted Environmental Concentration (PEC)
PEC is calculated according to the following formula:
PEC (μg/L) = (A*109*(100-R)/(365*P*V*D*100) = 1.37*10-6*A(100-R)
PEC = 7.54 x10-5 μg/L
Where:
A = 0.55 kg (total sold amount API in Sweden year 2022, data from IQVIA). Reduction of A may be justified based on metabolism data.
R = 0% removal rate (conservatively, it has been assumed there is no loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)
P = number of inhabitants in Sweden = 10 *106
V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Reference 1)
D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Reference 1)
Predicted No Effect Concentration (PNEC)
Ecotoxicological studies
Green Algae:
No data
Water flea:
Acute toxicity
No data
Water flea:
Chronic toxicity
No Data
Fish:
Acute toxicity
No data
Chronic toxicity
No Data
Other ecotoxicity data:
No data
PNEC cannot be calculated because data is not available for all three (algae, crustacean and fish) of the short-term toxicity endpoints.
Environmental risk classification (PEC/PNEC ratio)
According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of ambrisentan is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 μg/L (Reference 2).
Degradation
Biotic degradation
Ready degradability:
No data
Inherent degradability:
No Data
Abiotic degradation
Hydrolysis:
No data
Photolysis:
No data
Justification of chosen degradation phrase:
There are no degradation available for ambrisentan. The phrase “The potential for persistence of ambrisentan cannot be excluded, due to lack of data” is thus chosen.
Bioaccumulation
Partitioning coefficient:
Log Dowcalculated = 0.56 @ pH 7 (Reference 4)
Justification of chosen bioaccumulation phrase:
Since log Dow < 4, the substance has low potential for bioaccumulation.
Excretion (metabolism)
Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S) to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan (21%) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide (5%). The binding affinity of 4-hydroxymethyl ambrisentan for the human endothelin receptor is 65-fold less than ambrisentan. Therefore at concentrations observed in the plasma (approximately 4% relative to parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological activity of ambrisentan.
Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. Plasma elimination half-life in humans ranges from 13.6 to 16.5 hours (Reference 3).
References
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ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.
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FASS.se, Environmental Classification of Pharmaceuticals. 2012 (v 3.0) Guidance for pharmaceutical companies.
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Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Volibis (Ambrisentan). GlaxoSmithKline plc, October 2014.
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Chemaxon /LogD. December 2014. Instant J Chem, ChemAxon Ltd.