Biodegradability and transformation of human pharmaceutical active ingredients in environmentally relevant test systems

Abstract

Human pharmaceutical active ingredients that are orally or parenterally administered may be metabolised in the body and after excretion may be further transformed in the receiving environmental compartments. The optimal outcome from an environmental point of view—complete mineralisation—is rarely observed. Small molecule pharmaceuticals are commonly not readily biodegradable according to Organisation for Economic Cooperation and Development (OECD) 301 tests. However, primary transformation is often observed. To gain information on the transformation of active ingredients in the environment, long-term studies like transformation in aquatic water/sediment systems according to OECD guideline 308 are required for the environmental risk assessment for human active pharmaceutical ingredients. Studies received until mid 2010 as part of the dossiers for marketing authorisation applications were evaluated concerning transformation products. The evaluation revealed that in 70 % of the studies, at least one transformation product (TP) is formed above 10 % of the originally applied dose, but in only 26 % of the studies are all TP identified. The evaluation also revealed that some TP of pharmaceutical active ingredients show a considerably longer DT50 compared to the parent compound. An example is the TP (val)sartan acid that is formed from an antihypertensive compound.

Selective serotonin reuptake inhibitors and β‐blocker transformation products may not pose a significant risk of toxicity to aquatic organisms in wastewater effluent‐dominated receiving waters

“…The method for predicted metabolites has been employed for active pharmaceutical ingredient submission requirements from 2002 onward as per OECD Guidelines 302 and 308. Berkner and Thierbach () conducted a review on chemical submissions following these degradation guidelines as of 2010. They found that of 33 studies that used the guideline‐recommended radiolabeled analytes, in 70% of the studies, at least 1 TP is formed above 10% of the originally applied dose, but in only 26% of the studies are all TPs identified.…”

Occurrence, ecotoxicological effects and risk assessment of antihypertensive pharmaceutical residues in the aquatic environment - A review

“…According to Berkner and Thierbach (2014), metabolites and TP should be of higher ecotoxicological concern than the parent compounds, because, in some cases, they are even more persistent and/or more mobile than the parent compounds. In spite of this, regarding antihypertensives metabolites, to the author's knowledge, only Escher et al (2006) were able to model EC 50 values for atenolol, metoprolol and propranolol human metabolites, using a baseline quantitative structure-activity relationship (QSAR) for 24-h algal chlorophyll fluorescence test.…”

Peer Review #2 of "Effects of guanylurea, the transformation product of the antidiabetic drug metformin, on the health of brown trout (Salmo trutta f. fario) (v0.1)"

“…These tests serve for the identification and quantification of transformation products that are formed at a percentage of ≥ 10 % of the applied dose of the parent compound (OECD 2002). Berkner and Thierbach (2014) examined the OECD 308 tests of dossiers for marketing authorisation applications of pharmaceuticals and found 70 % of the tests to show a formation of at least one transformation product, but only 26 % of the studies to identify this product. These results reveal a significant data gap for transformation products of pharmaceuticals formed in the environment.…”

“…For example, Schlüter-Vorberg et al (2015) showed that carboxy-acyclovir, a transformation product of the antiviral drug acyclovir formed in sewage treatment plants, was much more toxic than its parent compound. Valsartanic acid, the transformation product of the antihypertensive drug valsartan formed in the activated sludge of waste water treatment plants, was shown to be much more persistent than its parent compound (Berkner & Thierbach 2014;Helbling et al 2010). An example for a transformation product with a high formation yield is guanylurea.…”