3. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J (2014) Clinical development
success rates for investigational drugs. Nat Biotechnol 32(1):40–51. https://doi.org/10.1038/
nbt.2786
4. Shultz MD (2019) Two decades under the influence of the rule of five and the changing
properties of approved oral drugs. J Med Chem 62(4):1701–1714. https://doi.org/10.1021/acs.
jmedchem.8b00686
5. Testa B, Crivori P, Reist M, Carrupt P-A (2000) The influence of lipophilicity on the
pharmacokinetic behavior of drugs: concepts and examples. Persp Drug Discov Des 19
(1):179–211. https://doi.org/10.1023/A:1008741731244
6. Sakaeda T, Okamura N, Nagata S, Yagami T, Horinouchi M, Okumura K, Yamashita F,
Hashida M (2001) Molecular and pharmacokinetic properties of 222 commercially available
oral drugs in humans. Biol Pharm Bull 24(8):935–940. https://doi.org/10.1248/bpb.24.935
7. Charifson PS, Walters WP (2014) Acidic and basic drugs in medicinal chemistry: a perspective. J Med Chem 57(23):9701–9717. https://doi.org/10.1021/jm501000a
8. Smith DA, Beaumont K, Maurer TS, Di L (2015) Volume of distribution in drug design. J Med
Chem 58(15):5691–5698. https://doi.org/10.1021/acs.jmedchem.5b00201
9. Trainor GL (2007) The importance of plasma protein binding in drug discovery. Expert Opin
Drug Discovery 2(1):51–64. https://doi.org/10.1517/17460441.2.1.51
10. Jansson R, Bredberg U, Ashton M (2008) Prediction of drug tissue to plasma concentration
ratios using a measured volume of distribution in combination with lipophilicity. J Pharm Sci
97(6):2324–2339. https://doi.org/10.1002/jps.21130
11. Hosey CM, Broccatelli F, Benet LZ (2014) Predicting when biliary excretion of parent drug is
a major route of elimination in humans. AAPS J 16(5):1085–1096. https://doi.org/10.1208/
s12248-014-9636-1
12. Paine SW, Barton P, Bird J, Denton R, Menochet K, Smith A, Tomkinson NP, Chohan KK
(2010) A rapid computational filter for predicting the rate of human renal clearance. J Mol
Graph Model 29(4):529–537. https://doi.org/10.1016/j.jmgm.2010.10.003
13. Di L (2014) The role of drug metabolizing enzymes in clearance. Expert Opin Drug Metab
Toxicol 10(3):379–393. https://doi.org/10.1517/17425255.2014.876006
14. Directive WF (2003) Common implementation strategy for the water framework directive
(2000/60/EC). Guidance document (7)
15. Carvalho RN, Ceriani L, Ippolito A, Lettieri T (2015) Development of the first watch list under
the environmental quality standards directive. JRC Science Hub, Brussels
16. Directive E (2013) Directive 2013/39/EU of the European Parliament and of the Council of
12 August 2013 amending Directives 2000/60/EC and 2008/105/EC as regards priority substances in the field of water policy. Off J Eur Union L 226:1–17
17. European, Commission (2019) Communication from the Commission to the European Parliament, the Council and the European Economic and Social Committee European Union
Strategic Approach to Pharmaceuticals in the Environment. Brussels, 1132019 COM (2019)
128 final
18. Decision E (2015) 495/2015, Commission Implementing Decision (EU) 2015/495 of
20 March 2015 establishing a watch list of substances for Union-wide monitoring in the
field of water policy pursuant to Directive 2008/105/EC of the European Parliament and of the
Council. Off J Eur Union L 78:40–42
19. Union E (2018) Commission Implementing Decision (EU) 2018/840 of 5 June 2018
establishing a watch list of substances for Union-wide monitoring in the field of water policy
pursuant to Directive 2008/105/EC of the European Parliament and of the Council and
repealing Commission Implementing Decision (EU) 2015/495. Off J Eur Union 141:9–12
20. Gómez Cortés L, Marinov D, Sanseverino I, Navarro Cuenca A, Niegowska M, Porcel
Rodriguez E, Lettieri T (2019) Selection of substances for the 3rd Watch List under the
Water Framework Directive (draft). European Comission, JRC Technical Reports
21. Walter S, Mitkidis K (2018) The risk assessment of pharmaceuticals in the environment: EU
and US regulatory approach. Eur J Risk Regul 9(3):527–547
26
N. Montemurro et al.
success rates for investigational drugs. Nat Biotechnol 32(1):40–51. https://doi.org/10.1038/
nbt.2786
4. Shultz MD (2019) Two decades under the influence of the rule of five and the changing
properties of approved oral drugs. J Med Chem 62(4):1701–1714. https://doi.org/10.1021/acs.
jmedchem.8b00686
5. Testa B, Crivori P, Reist M, Carrupt P-A (2000) The influence of lipophilicity on the
pharmacokinetic behavior of drugs: concepts and examples. Persp Drug Discov Des 19
(1):179–211. https://doi.org/10.1023/A:1008741731244
6. Sakaeda T, Okamura N, Nagata S, Yagami T, Horinouchi M, Okumura K, Yamashita F,
Hashida M (2001) Molecular and pharmacokinetic properties of 222 commercially available
oral drugs in humans. Biol Pharm Bull 24(8):935–940. https://doi.org/10.1248/bpb.24.935
7. Charifson PS, Walters WP (2014) Acidic and basic drugs in medicinal chemistry: a perspective. J Med Chem 57(23):9701–9717. https://doi.org/10.1021/jm501000a
8. Smith DA, Beaumont K, Maurer TS, Di L (2015) Volume of distribution in drug design. J Med
Chem 58(15):5691–5698. https://doi.org/10.1021/acs.jmedchem.5b00201
9. Trainor GL (2007) The importance of plasma protein binding in drug discovery. Expert Opin
Drug Discovery 2(1):51–64. https://doi.org/10.1517/17460441.2.1.51
10. Jansson R, Bredberg U, Ashton M (2008) Prediction of drug tissue to plasma concentration
ratios using a measured volume of distribution in combination with lipophilicity. J Pharm Sci
97(6):2324–2339. https://doi.org/10.1002/jps.21130
11. Hosey CM, Broccatelli F, Benet LZ (2014) Predicting when biliary excretion of parent drug is
a major route of elimination in humans. AAPS J 16(5):1085–1096. https://doi.org/10.1208/
s12248-014-9636-1
12. Paine SW, Barton P, Bird J, Denton R, Menochet K, Smith A, Tomkinson NP, Chohan KK
(2010) A rapid computational filter for predicting the rate of human renal clearance. J Mol
Graph Model 29(4):529–537. https://doi.org/10.1016/j.jmgm.2010.10.003
13. Di L (2014) The role of drug metabolizing enzymes in clearance. Expert Opin Drug Metab
Toxicol 10(3):379–393. https://doi.org/10.1517/17425255.2014.876006
14. Directive WF (2003) Common implementation strategy for the water framework directive
(2000/60/EC). Guidance document (7)
15. Carvalho RN, Ceriani L, Ippolito A, Lettieri T (2015) Development of the first watch list under
the environmental quality standards directive. JRC Science Hub, Brussels
16. Directive E (2013) Directive 2013/39/EU of the European Parliament and of the Council of
12 August 2013 amending Directives 2000/60/EC and 2008/105/EC as regards priority substances in the field of water policy. Off J Eur Union L 226:1–17
17. European, Commission (2019) Communication from the Commission to the European Parliament, the Council and the European Economic and Social Committee European Union
Strategic Approach to Pharmaceuticals in the Environment. Brussels, 1132019 COM (2019)
128 final
18. Decision E (2015) 495/2015, Commission Implementing Decision (EU) 2015/495 of
20 March 2015 establishing a watch list of substances for Union-wide monitoring in the
field of water policy pursuant to Directive 2008/105/EC of the European Parliament and of the
Council. Off J Eur Union L 78:40–42
19. Union E (2018) Commission Implementing Decision (EU) 2018/840 of 5 June 2018
establishing a watch list of substances for Union-wide monitoring in the field of water policy
pursuant to Directive 2008/105/EC of the European Parliament and of the Council and
repealing Commission Implementing Decision (EU) 2015/495. Off J Eur Union 141:9–12
20. Gómez Cortés L, Marinov D, Sanseverino I, Navarro Cuenca A, Niegowska M, Porcel
Rodriguez E, Lettieri T (2019) Selection of substances for the 3rd Watch List under the
Water Framework Directive (draft). European Comission, JRC Technical Reports
21. Walter S, Mitkidis K (2018) The risk assessment of pharmaceuticals in the environment: EU
and US regulatory approach. Eur J Risk Regul 9(3):527–547
26
N. Montemurro et al.