Download Enalapril Maleate

Environmental Risk Assessment Data
Enalapril Maleate
Enalapril maleate is used in the AstraZeneca drug product Lexxel for the treatment of
hypertension. It is a fixed-dose combination of the ACE inhibitor enalapril maleate and the
highly vascular selective calcium antagonist felodipine.
Enalapril maleate is a pro-drug which is hydrolysed to the active compound enalaprilat, the
main active converting enzyme inhibitor. Excretion of enalaprilat and enalapril is primarily
renal. Approximately 94% of the dose is recovered in the urine and faeces as enalaprilat or
enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent
of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than
enalaprilat.
Since both enalapril and enalaprilat are excreted from the human body, both compounds
were aimed to be taken into account in the PEC evaluation. However, very limited ecotoxicity
data are available for enalapril or enalaprilat. Therefore, the Predicted Environmental
Concentration (PEC) / Predicted No Effect Concentration (PNEC) has not been determined.
No information is available concerning the biodegradability, however enalapril is not
predicted to bioaccumulate in aquatic organisms.
Predicted Environmental Concentration (PEC)
The PEC is based on the following data:
PEC (µg/L) = (A*109*(100-R))/(365*P*V*D*100)
A (kg/year) = total patient consumption of enalapril (active moiety) in the European country
with the highest per capita use in 2010 (Source: IMS Health)
R (%) = % removal during wastewater (sewage) treatment (due to loss by adsorption to
sludge particles, by volatilisation, hydrolysis or biodegradation). For enalapril, it is assumed
that R = 0 as a worst case.
P = number of inhabitants in the European country with the highest per capita use of
enalapril in 2010 (Source: IMS Health).
A/P = 2.8 x 10-4 kg/inhabitant
V (L/day) = volume of wastewater per capita and day = 200 (European Medicines Agency
(EMA) default value (Ref. 1))
D = factor for dilution of waste water by surface water flow = 10 (EMA default value)
(Note: The factor 109 in the equation above converts the quantity used from kg to μg)
PEC = 3.8 x 10-1 µg/L
(Note: Whilst enalapril is metabolised in humans, little is known about the ecotoxicity of the
metabolites. Hence, as a worst case, for the purpose of this calculation, it is assumed that
100% of excreted metabolites have the same ecotoxicity as parent enalapril)
Predicted No Effect Concentration (PNEC)
Short-term testing is available for the crustacean Thamnocephalus platyrus.. However,
species from three trophic levels are normally used to calculate a PNEC in accordance with
the ECHA guideline (Ref. 2); therefore a PNEC has not been determined.
PEC/PNEC
PEC = 3.8 x 10-1 µg/L
PNEC = Not determined
February 2012
As the PNEC is not calculated, the PEC/PNEC has not been determined.
References
1. Committee for Medicinal Products for Human Use (CHMP); Guideline on the
Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006,
Ref EMEA/CPMP/SWP/4447/00.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/1
0/WC500003978.pdf
2. [ECHA] European Chemicals Agency. 2008. Guidance on Information Requirements
and Chemical Safety Assessment.
http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_
en.htm
Aquatic Toxicity Data - Enalapril
Endpoint
Species
LC50
Thamnocephalus
platyurus
Common
Name
Beaver-tail
Fairy Shrimp
Method
Time
Result
Thamnotoxkit
24 h
184 mg/L
Note 1,2,3
Physical Chemistry Data - Enalapril
Endpoint
Solubility Water
Method
Potentiometric
Method
Test Conditions
pH 1, 25oC
pH 5, 25oC
pH 6.8, 25oC
pH 7.4, 25oC
Result
3300 g/L
24 g/L
430 g/L
1700 g/L
Note 3,4
Partition
Coefficient
Octanol Water
Dissociation
Constant
-
o
25 C
Log P = 0.16
Note 3,4
-
25oC
pKa(1) = 2.97
pKa(2) = 5.35
Note 3,5
Note 1: Results are expressed as nominal concentrations
Note 2: Data from Nalecz-Jawecki G., Persoone G.; Toxicity of Selected Pharmaceuticals to the
Anostracan Crustacean Thamnocephalus platyurus. Environ. Sci. Pollut. Res. 2006, 13, 22-27.
Note 3: This study pre-dates current ERA regulatory requirements and may not have been
undertaken to standardised test guidelines.
Note 4: Data from Avdeef A., Berger C.M.; pH-Metric Solubility. 3. Dissolution Titration Template
Method for Solubility Determination. Eur. J. Pharm. Sci. 2001, 14, 281-291.
Note 5: These data are taken from Ip D.P., Brenner G.S.; Enalapril Maleate. Anal. Profiles Drug Subst.
1987, 16, 207-243.