よむ、つかう、まなぶ。
資料３－３ ストラテラカプセル及びストラテラ内用液にて検出された新規ニトロソアミンの限度値について（企業見解）［7.8MB］ (22 ページ)
出典
| 公開元URL | https://www.mhlw.go.jp/stf/newpage_42464.html |
| 出典情報 | 薬事審議会 医薬品等安全対策部会安全対策調査会（令和6年度第5回 8／28）《厚生労働省》 |
ページ画像
ダウンロードした画像を利用する際は「出典情報」を明記してください。
低解像度画像をダウンロード
プレーンテキスト
資料テキストはコンピュータによる自動処理で生成されており、完全に資料と一致しない場合があります。
テキストをコピーしてご利用いただく際は資料と付け合わせてご確認ください。
Chemical Research in Toxicology
pubs.acs.org/crt
authorisation/referral-procedures/nitrosamine-impurities (accessed
on 29th November 2023).
(10) Control of Nitrosamine Impurities in Human Drugs; FDA, 2023.
https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/control-nitrosamine-impurities-human-drugs (accessed
on 05 April 2024).
(11) Moser, J.; Ashworth, I. W.; Harris, L.; Hillier, M. C.; Nanda, K.
K.; Scrivens, G. N-Nitrosamine Formation in Pharmaceutical Solid
Drug Products: Experimental Observations. J. Pharm. Sci. 2023, 112
(5), 1255−1267.
(12) Schlingemann, J.; Burns, M. J.; Ponting, D. J.; Martins Avila, C.;
Romero, N. E.; Jaywant, M. A.; Smith, G. F.; Ashworth, I. W.; Simon,
S.; Saal, C.; et al. The Landscape of Potential Small and Drug
Substance Related Nitrosamines in Pharmaceuticals. J. Pharm. Sci.
2023, 112, 1287. From NLM Publisher.
(13) Thresher, A.; Foster, R.; Ponting, D. J.; Stalford, S. A.; Tennant,
R. E.; Thomas, R. Are all nitrosamines concerning? A review of
mutagenicity and carcinogenicity data. Regul. Toxicol. Pharmacol.
2020, 116, No. 104749.
(14) Bercu, J. P.; Masuda-Herrera, M.; Trejo-Martin, A.; Sura, P.;
Jolly, R.; Kenyon, M.; Thomas, R.; Ponting, D. J.; Snodin, D.; Tuschl,
G. Acceptable intakes (AIs) for 11 small molecule N-nitrosamines
(NAs). Regul. Toxicol. Pharmacol. 2023, 142, No. 105415. From
NLM Publisher.), 142.
(15) Woolley, D. R.; Cross, K. P.; Johnson, G. E. Risk
(Re)Assessment of N-Methyl-N-Nitrosophenethylamine for Use in
Computing Acceptable Intake Levels of N-Nitrosamine Drug
Substance-Related Impurities. In Toxicologist, a Supplement to
Toxicological Science, 2023, Abstract #4477.
(16) Oliveiria, A. A.; Martins-Avila, C.; Ponting, D. J.. Collaborative
Analysis of Complex Nitrosamines. In Toxicologist, a Supplement to
Toxicological Sciences, 2023, Abstract #5063.
(17) Cross, K. P.; Ponting, D. J. Developing structure-activity
relationships for N-nitrosamine activity. Comput. Toxicol. 2021, 20,
No. 100186.
(18) Dobo, K. L.; Kenyon, M. O.; Dirat, O.; Engel, M.; Fleetwood,
A.; Martin, M.; Mattano, S.; Musso, A.; McWilliams, J. C.;
Papanikolaou, A.; et al. Practical and Science-Based Strategy for
Establishing Acceptable Intakes for Drug Product N-Nitrosamine
Impurities. Chem. Res. Toxicol. 2022, 35 (3), 475−489.
(19) Thomas, R.; Tennant, R. E.; Oliveira, A. A. F.; Ponting, D. J.
What Makes a Potent Nitrosamine? Statistical Validation of ExpertDerived Structure−Activity Relationships. Chem. Res. Toxicol. 2022,
35 (11), 1997−2013.
(20) Wenzel, J.; Schmidt, F.; Blumrich, M.; Amberg, A.; Czich, A.
Predicting DNA-Reactivity of N-Nitrosamines: A Quantum Chemical
Approach. Chem. Res. Toxicol. 2022, 35 (11), 2068−2084.
(21) Ponting, D. J.; Dobo, K. L.; Kenyon, M. O.; Kalgutkar, A. S.
Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines
Derived from Active Pharmaceutical Ingredients. J. Med. Chem. 2022,
65, 15584 DOI: 10.1021/acs.jmedchem.2c01498.
(22) Recommended Acceptable Intake Limits for Nitrosamine Drug
Substance Related Impurities (NDSRIs) Guidance for Industry. https://
www.fda.gov/media/170794/download (accessed on 2nd February
2024).
(23) Personal communication Suman Chakravarti. CEO multicase.
(24) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,
G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.;
Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J.
V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.;
Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson,
T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;
Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H. et al.
Gaussian 16, Revision B.01; Gaussian, Inc, 2018.
(25) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the damping
function in dispersion corrected density functional theory. J. Comput.
Chem. 2011, 32, 1456−1465.
Article
(26) Becke, A. D. Density-functional thermochemistry. III. The role
of exact exchange. J. Chem. Phys. 1993, 98 (7), 5648−5652.
(27) Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti
correlation-energy formula into a functional of the electron density.
Phys. Rev. B 1988, 37 (2), 785−789.
(28) Ma, G.; Yu, H.; Xu, T.; Wei, X.; Chen, J.; Lin, H.; Schüürmann,
G. Computational Insight into the Activation Mechanism of
Carcinogenic N’-Nitrosonornicotine (NNN) Catalyzed by Cytochrome P450. Environ. Sci. Technol. 2018, 52 (20), 11838−11847.
(29) Barone, V.; Cossi, M. Quantum Calculation of Molecular
Energies and Energy Gradients in Solution by a Conductor Solvent
Model. J. Phys. Chem. A 1998, 102 (11), 1995−2001.
(30) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies,
structures, and electronic properties of molecules in solution with the
C-PCM solvation model. J. Comput. Chem. 2003, 24 (6), 669−681.
(31) Laidler, K. J.; King, M. C. Development of transition-state
theory. J. Phys. Chem. 1983, 87 (15), 2657−2664.
(32) Vaz, A. D. N.; Coon, M. J. On the Mechanism of Action of
Cytochrome P450: Evaluation of Hydrogen Abstraction in OxygenDependent Alcohol Oxidation. Biochemistry 1994, 33 (21), 6442−
6449.
(33) Puetz, H.; Puchl’ová, E.; Vranková, K.; Hollmann, F.
Biocatalytic Oxidation of Alcohols. Catalysts 2020, 10 (952), 952.
(34) Li, Y.; Hecht, S. S. Metabolic Activation and DNA Interactions
of Carcinogenic N-Nitrosamines to Which Humans Are Commonly
Exposed. Int. J. Mol. Sci. 2022, 23, 4559.
(35) The activation energies N-oxidation transition state in high-spin
and low-spin states are 12.9 and 17.4 kcal/mol respectively. The
activation energies N-CH3 hydroxylation of N(CH3)2 group transition
state in high-spin and low-spin states are 9.2 and 7.4 kcal/mol
respectively. The activation energies N-CH3 hydroxylation of
N(CH2)-NNO group transition state in high-spin and low-spin states
are 19.0 and 21.1 kcal/mol respectively.
(36) (a) Confer, M. P.; Qu, T.; Rupar, P. A.; Dixon, D. A.
Composite Correlated Molecular Orbital Theory Calculations of Ring
Strain for Use in Predicting Polymerization Reactions. ChemPhysChem 2022, 23 (9), No. e202200133. (b) Snodin, D. J.; TrejoMartin, A.; Ponting, D. J.; Smith, G. F.; Czich, A.; Cross, K.; Custer,
L.; Elloway, J.; Greene, N.; Kalgutkar, A. S.; et al. Mechanisms of
Nitrosamine Mutagenicity and Their Relationship to Rodent
Carcinogenic Potency. Chem. Res. Tox. 2024, 37 (2), 181−198.
(37) Ripa, L.; Mee, C.; Sjö, P.; Shamovsky, I. Theoretical Studies of
the Mechanism of N-Hydroxylation of Primary Aromatic Amines by
Cytochrome P450 1A2: Radicaloid or Anionic? Chem. Res. Toxicol.
2014, 27, 265−278.
(38) Ji, L.; Schrmann, G. Model and Mechanism: N-Hydroxylation
of Primary Aromatic Amines by Cytochrome P450. Angew. Chem., Int.
Ed. 2013, 52, 744−748.
(39) Combourieu, B.; Poupin, P.; Besse, P.; Sancelme, M.;
Veschambre, H.; Truffaut, N.; Delort, A.-M. Thiomorpholine and
morpholine oxidation by a cytochrome P450 in Mycobacterium
Aurum MO1. Evidence of the intermediates by in situ 1H NMR.
Biodegradation 1998, 9, 433−442.
(40) Heydt-Zapf, G.; Haubner, R.; Preussmann, R.; Eisenbrand, G.
Metabolism of carcinogenic and non-carcinogenic N-nitroso-Nmethylaminopyridines. n. Investigations in vivo. Carcinogenesis 1983,
4 (6), 729−731.
(41) Heydt, G.; Eisenbrand, G.; Preussmann, R. Metabolism of
carcinogenic and non-carcinogenic N-nitroso-N-methylaminopyridines. I. Investigations in vitro. Carcinogenesis 1982, 3 (4), 445−448.
(42) Breton, G. W. DFT study of ortho, meta and para−pyridyl
cations Pyridynium found? Comput. Theor. Chem. 2018, 1133, 51−57.
(43) Kostal, J.; Voutchkova-Kostal, A. Quantum-Mechanical
Approach to Predicting the Carcinogenic Potency of N-Nitroso
Impurities in Pharmaceuticals. Chem. Res. Toxicol. 2023, 36 (2), 291−
304.
1022
22 / 34 ページ
https://doi.org/10.1021/acs.chemrestox.4c00087
Chem. Res. Toxicol. 2024, 37, 1011−1022
pubs.acs.org/crt
authorisation/referral-procedures/nitrosamine-impurities (accessed
on 29th November 2023).
(10) Control of Nitrosamine Impurities in Human Drugs; FDA, 2023.
https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/control-nitrosamine-impurities-human-drugs (accessed
on 05 April 2024).
(11) Moser, J.; Ashworth, I. W.; Harris, L.; Hillier, M. C.; Nanda, K.
K.; Scrivens, G. N-Nitrosamine Formation in Pharmaceutical Solid
Drug Products: Experimental Observations. J. Pharm. Sci. 2023, 112
(5), 1255−1267.
(12) Schlingemann, J.; Burns, M. J.; Ponting, D. J.; Martins Avila, C.;
Romero, N. E.; Jaywant, M. A.; Smith, G. F.; Ashworth, I. W.; Simon,
S.; Saal, C.; et al. The Landscape of Potential Small and Drug
Substance Related Nitrosamines in Pharmaceuticals. J. Pharm. Sci.
2023, 112, 1287. From NLM Publisher.
(13) Thresher, A.; Foster, R.; Ponting, D. J.; Stalford, S. A.; Tennant,
R. E.; Thomas, R. Are all nitrosamines concerning? A review of
mutagenicity and carcinogenicity data. Regul. Toxicol. Pharmacol.
2020, 116, No. 104749.
(14) Bercu, J. P.; Masuda-Herrera, M.; Trejo-Martin, A.; Sura, P.;
Jolly, R.; Kenyon, M.; Thomas, R.; Ponting, D. J.; Snodin, D.; Tuschl,
G. Acceptable intakes (AIs) for 11 small molecule N-nitrosamines
(NAs). Regul. Toxicol. Pharmacol. 2023, 142, No. 105415. From
NLM Publisher.), 142.
(15) Woolley, D. R.; Cross, K. P.; Johnson, G. E. Risk
(Re)Assessment of N-Methyl-N-Nitrosophenethylamine for Use in
Computing Acceptable Intake Levels of N-Nitrosamine Drug
Substance-Related Impurities. In Toxicologist, a Supplement to
Toxicological Science, 2023, Abstract #4477.
(16) Oliveiria, A. A.; Martins-Avila, C.; Ponting, D. J.. Collaborative
Analysis of Complex Nitrosamines. In Toxicologist, a Supplement to
Toxicological Sciences, 2023, Abstract #5063.
(17) Cross, K. P.; Ponting, D. J. Developing structure-activity
relationships for N-nitrosamine activity. Comput. Toxicol. 2021, 20,
No. 100186.
(18) Dobo, K. L.; Kenyon, M. O.; Dirat, O.; Engel, M.; Fleetwood,
A.; Martin, M.; Mattano, S.; Musso, A.; McWilliams, J. C.;
Papanikolaou, A.; et al. Practical and Science-Based Strategy for
Establishing Acceptable Intakes for Drug Product N-Nitrosamine
Impurities. Chem. Res. Toxicol. 2022, 35 (3), 475−489.
(19) Thomas, R.; Tennant, R. E.; Oliveira, A. A. F.; Ponting, D. J.
What Makes a Potent Nitrosamine? Statistical Validation of ExpertDerived Structure−Activity Relationships. Chem. Res. Toxicol. 2022,
35 (11), 1997−2013.
(20) Wenzel, J.; Schmidt, F.; Blumrich, M.; Amberg, A.; Czich, A.
Predicting DNA-Reactivity of N-Nitrosamines: A Quantum Chemical
Approach. Chem. Res. Toxicol. 2022, 35 (11), 2068−2084.
(21) Ponting, D. J.; Dobo, K. L.; Kenyon, M. O.; Kalgutkar, A. S.
Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines
Derived from Active Pharmaceutical Ingredients. J. Med. Chem. 2022,
65, 15584 DOI: 10.1021/acs.jmedchem.2c01498.
(22) Recommended Acceptable Intake Limits for Nitrosamine Drug
Substance Related Impurities (NDSRIs) Guidance for Industry. https://
www.fda.gov/media/170794/download (accessed on 2nd February
2024).
(23) Personal communication Suman Chakravarti. CEO multicase.
(24) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,
G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.;
Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J.
V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.;
Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson,
T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;
Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H. et al.
Gaussian 16, Revision B.01; Gaussian, Inc, 2018.
(25) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the damping
function in dispersion corrected density functional theory. J. Comput.
Chem. 2011, 32, 1456−1465.
Article
(26) Becke, A. D. Density-functional thermochemistry. III. The role
of exact exchange. J. Chem. Phys. 1993, 98 (7), 5648−5652.
(27) Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti
correlation-energy formula into a functional of the electron density.
Phys. Rev. B 1988, 37 (2), 785−789.
(28) Ma, G.; Yu, H.; Xu, T.; Wei, X.; Chen, J.; Lin, H.; Schüürmann,
G. Computational Insight into the Activation Mechanism of
Carcinogenic N’-Nitrosonornicotine (NNN) Catalyzed by Cytochrome P450. Environ. Sci. Technol. 2018, 52 (20), 11838−11847.
(29) Barone, V.; Cossi, M. Quantum Calculation of Molecular
Energies and Energy Gradients in Solution by a Conductor Solvent
Model. J. Phys. Chem. A 1998, 102 (11), 1995−2001.
(30) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies,
structures, and electronic properties of molecules in solution with the
C-PCM solvation model. J. Comput. Chem. 2003, 24 (6), 669−681.
(31) Laidler, K. J.; King, M. C. Development of transition-state
theory. J. Phys. Chem. 1983, 87 (15), 2657−2664.
(32) Vaz, A. D. N.; Coon, M. J. On the Mechanism of Action of
Cytochrome P450: Evaluation of Hydrogen Abstraction in OxygenDependent Alcohol Oxidation. Biochemistry 1994, 33 (21), 6442−
6449.
(33) Puetz, H.; Puchl’ová, E.; Vranková, K.; Hollmann, F.
Biocatalytic Oxidation of Alcohols. Catalysts 2020, 10 (952), 952.
(34) Li, Y.; Hecht, S. S. Metabolic Activation and DNA Interactions
of Carcinogenic N-Nitrosamines to Which Humans Are Commonly
Exposed. Int. J. Mol. Sci. 2022, 23, 4559.
(35) The activation energies N-oxidation transition state in high-spin
and low-spin states are 12.9 and 17.4 kcal/mol respectively. The
activation energies N-CH3 hydroxylation of N(CH3)2 group transition
state in high-spin and low-spin states are 9.2 and 7.4 kcal/mol
respectively. The activation energies N-CH3 hydroxylation of
N(CH2)-NNO group transition state in high-spin and low-spin states
are 19.0 and 21.1 kcal/mol respectively.
(36) (a) Confer, M. P.; Qu, T.; Rupar, P. A.; Dixon, D. A.
Composite Correlated Molecular Orbital Theory Calculations of Ring
Strain for Use in Predicting Polymerization Reactions. ChemPhysChem 2022, 23 (9), No. e202200133. (b) Snodin, D. J.; TrejoMartin, A.; Ponting, D. J.; Smith, G. F.; Czich, A.; Cross, K.; Custer,
L.; Elloway, J.; Greene, N.; Kalgutkar, A. S.; et al. Mechanisms of
Nitrosamine Mutagenicity and Their Relationship to Rodent
Carcinogenic Potency. Chem. Res. Tox. 2024, 37 (2), 181−198.
(37) Ripa, L.; Mee, C.; Sjö, P.; Shamovsky, I. Theoretical Studies of
the Mechanism of N-Hydroxylation of Primary Aromatic Amines by
Cytochrome P450 1A2: Radicaloid or Anionic? Chem. Res. Toxicol.
2014, 27, 265−278.
(38) Ji, L.; Schrmann, G. Model and Mechanism: N-Hydroxylation
of Primary Aromatic Amines by Cytochrome P450. Angew. Chem., Int.
Ed. 2013, 52, 744−748.
(39) Combourieu, B.; Poupin, P.; Besse, P.; Sancelme, M.;
Veschambre, H.; Truffaut, N.; Delort, A.-M. Thiomorpholine and
morpholine oxidation by a cytochrome P450 in Mycobacterium
Aurum MO1. Evidence of the intermediates by in situ 1H NMR.
Biodegradation 1998, 9, 433−442.
(40) Heydt-Zapf, G.; Haubner, R.; Preussmann, R.; Eisenbrand, G.
Metabolism of carcinogenic and non-carcinogenic N-nitroso-Nmethylaminopyridines. n. Investigations in vivo. Carcinogenesis 1983,
4 (6), 729−731.
(41) Heydt, G.; Eisenbrand, G.; Preussmann, R. Metabolism of
carcinogenic and non-carcinogenic N-nitroso-N-methylaminopyridines. I. Investigations in vitro. Carcinogenesis 1982, 3 (4), 445−448.
(42) Breton, G. W. DFT study of ortho, meta and para−pyridyl
cations Pyridynium found? Comput. Theor. Chem. 2018, 1133, 51−57.
(43) Kostal, J.; Voutchkova-Kostal, A. Quantum-Mechanical
Approach to Predicting the Carcinogenic Potency of N-Nitroso
Impurities in Pharmaceuticals. Chem. Res. Toxicol. 2023, 36 (2), 291−
304.
1022
22 / 34 ページ
https://doi.org/10.1021/acs.chemrestox.4c00087
Chem. Res. Toxicol. 2024, 37, 1011−1022