programs in the search for chemical structures with low affinity for drugmetabolizing enzymes – while maintaining satisfactory properties in all other
disciplines – reflects the impact of metabolic clearance in the optimization cycle
during all stages until nomination of a candidate for preclinical development. If renal
and biliary excretion are negligible pathways, it is the intrinsic metabolic clearance
of a compound that has a large influence on the size of the human efficacious dose
and eventually on the amount of intact drug reaching the sewage plant. Suboptimal
drugs require not only a high dose, but they also suffer from the need for frequent
dosing in order to ensure sufficient coverage of the molecular target over the dosing
interval. When applying today’s standards for a successful drug with respect to dose
size and administration frequency, paracetamol with its thrice daily dosing of up to
1,000 mg each clearly ranks at the bottom of the favorite drugs’ list and automatically becomes a drug with high amounts in untreated sewage, either in form of intact
parent or as metabolites.
It is a legitimate question to ask whether novel small-molecule drugs can be
designed to be “environmentally friendly,” i.e., combining low therapeutic doses
with high biodegradability in the activated sludge treatment of the wastewater
treatment plant. The former aspect is undoubtedly addressed in research programs
at the pharmaceutical industry for a number of reasons: lower cost of goods,
competitive dose sizes and dosing intervals, and reduced risk of adverse effects
and drug-drug interactions. The latter, however, is – to the disappointment of
environmental scientists – not among the compound optimization criteria. Designing
compounds with structural elements susceptible to rapid and efficient microbial
degradation will be counterproductive. Too large are the similarities between
xenobiotic-recognizing enzymes (hydrolytic, oxidative, and conjugative ones)
between the human body and microbial communities.
5 Environmental Regulatory Perspective in the European
Union
Drugs that have been absorbed to reach systemic circulation are metabolized and
subsequently excreted through the bodily wastes as a mixture of parent compound
and the metabolites generated in the target organism. Finally, the complex mixture is
discharged through the sewage system and often, but not always, treated in wastewater plants, before the final effluents are released into the environment, where
further biotic and abiotic processes including sorption, photolysis, hydrolysis, and
biodegradation. Whereas excretion is the predominant input of drugs into the
environment, other pathways like inappropriate disposal, industrial spills, or manure
spread (particularly for veterinary drugs) should not be overlooked. From the
environmental point of view, the following facts of concern are worth considering:
12
N. Montemurro et al.
disciplines – reflects the impact of metabolic clearance in the optimization cycle
during all stages until nomination of a candidate for preclinical development. If renal
and biliary excretion are negligible pathways, it is the intrinsic metabolic clearance
of a compound that has a large influence on the size of the human efficacious dose
and eventually on the amount of intact drug reaching the sewage plant. Suboptimal
drugs require not only a high dose, but they also suffer from the need for frequent
dosing in order to ensure sufficient coverage of the molecular target over the dosing
interval. When applying today’s standards for a successful drug with respect to dose
size and administration frequency, paracetamol with its thrice daily dosing of up to
1,000 mg each clearly ranks at the bottom of the favorite drugs’ list and automatically becomes a drug with high amounts in untreated sewage, either in form of intact
parent or as metabolites.
It is a legitimate question to ask whether novel small-molecule drugs can be
designed to be “environmentally friendly,” i.e., combining low therapeutic doses
with high biodegradability in the activated sludge treatment of the wastewater
treatment plant. The former aspect is undoubtedly addressed in research programs
at the pharmaceutical industry for a number of reasons: lower cost of goods,
competitive dose sizes and dosing intervals, and reduced risk of adverse effects
and drug-drug interactions. The latter, however, is – to the disappointment of
environmental scientists – not among the compound optimization criteria. Designing
compounds with structural elements susceptible to rapid and efficient microbial
degradation will be counterproductive. Too large are the similarities between
xenobiotic-recognizing enzymes (hydrolytic, oxidative, and conjugative ones)
between the human body and microbial communities.
5 Environmental Regulatory Perspective in the European
Union
Drugs that have been absorbed to reach systemic circulation are metabolized and
subsequently excreted through the bodily wastes as a mixture of parent compound
and the metabolites generated in the target organism. Finally, the complex mixture is
discharged through the sewage system and often, but not always, treated in wastewater plants, before the final effluents are released into the environment, where
further biotic and abiotic processes including sorption, photolysis, hydrolysis, and
biodegradation. Whereas excretion is the predominant input of drugs into the
environment, other pathways like inappropriate disposal, industrial spills, or manure
spread (particularly for veterinary drugs) should not be overlooked. From the
environmental point of view, the following facts of concern are worth considering:
12
N. Montemurro et al.