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Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Review Article

The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

Author(s): Li Di*

Volume 20, Issue 2, 2019

Page: [91 - 102] Pages: 12

DOI: 10.2174/1389200219666180821094502

Abstract

Background: Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates and thioesters, as well as bioconverting prodrugs and soft drugs. The unique tissue distribution of CES enzymes provides great opportunities to design prodrugs or soft drugs for tissue targeting. Marked species differences in CES tissue distribution and catalytic activity are particularly challenging in human translation.

Methods: Review and summarization of CES fundamentals and applications in drug discovery and development.

Results: Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human intestine only expresses CES2. CES enzymes have moderate to high inter-individual variability and exhibit low to no expression in the fetus, but increase substantially during the first few months of life. The CES genes are highly polymorphic and some CES genetic variants show significant influence on metabolism and clinical outcome of certain drugs. Monkeys appear to be more predictive of human pharmacokinetics for CES substrates than other species. Low risk of clinical drug-drug interaction is anticipated for CES, although they should not be overlooked, particularly interaction with alcohols. CES enzymes are moderately inducible through a number of transcription factors and can be repressed by inflammatory cytokines.

Conclusion: Although significant advances have been made in our understanding of CESs, in vitro - in vivo extrapolation of clearance is still in its infancy and further exploration is needed. In vitro and in vivo tools are continuously being developed to characterize CES substrates and inhibitors.

Keywords: Carboxylesterases, CES1, CES2, prodrugs, soft drugs, tissue distribution, species differences, IVIVE, substrates, inhibitors, drug design.

Graphical Abstract
[1]
Yan, B. Carboxylesterases. Encycl. Drug Metab. Interact., 2012, 1, 423-456.
[2]
Laizure, S.C.; Herring, V.; Hu, Z.; Witbrodt, K.; Parker, R.B. The role of human carboxylesterases in drug metabolism: Have we overlooked their importance? Pharmacotherapy, 2013, 33, 210-222.
[3]
Hatfield, M.J.; Potter, P.M. Carboxylesterase inhibitors. Expert Opin. Ther. Pat., 2011, 21, 1159-1171.
[4]
Di, L.; Kerns, E.H. Drug-Like Properties: Concepts, Structure Design, and Methods; Elevier: London, UK, 2016.
[5]
Ettmayer, P.; Amidon, G.L.; Clement, B.; Testa, B. Lessons learned from marketed and investigational prodrugs. J. Med. Chem., 2004, 47, 2393-2404.
[6]
Merali, Z.; Ross, S.; Pare, G. The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect. Drug Metabol. Drug Interact., 2014, 29, 143-151.
[7]
Satoh, T.; Hosokawa, M. Structure, function and regulation of carboxylesterases. Chem. Biol. Interact., 2006, 162, 195-211.
[8]
Satoh, T.; Hosokawa, M. Carboxylesterases: Structure, function and polymorphism. Biomol. Ther., 2009, 17, 335-347.
[9]
Redinbo, M.R.; Bencharit, S.; Potter, P.M. Human carboxylesterase 1: From drug metabolism to drug discovery. Biochem. Soc. Trans., 2003, 31, 620-624.
[10]
Sweeney, R.E.; Maxwell, D.M. A theoretical model of the competition between hydrolase and carboxylesterase in protection against organophosphorus poisoning. Math. Biosci., 1999, 160, 175-190.
[11]
Broomfield, C.A.; Kirby, S.D. Progress on the road to new nerve agent treatments. J. Appl. Toxicol., 2001, 21, S43-S46.
[12]
Maxwell, D.M.; Brecht, K.M. Carboxylesterase: specificity and spontaneous reactivation of an endogenous scavenger for organophosphorus compounds. J. Appl. Toxicol., 2001, 21, S103-S107.
[13]
Bencharit, S.; Morton, C.L.; Xue, Y.; Potter, P.M.; Redinbo, M.R. Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme. Nat. Struct. Biol., 2003, 10, 349-356.
[14]
Wang, D-D.; Zou, L-W.; Jin, Q.; Hou, J.; Ge, G-B.; Yang, L. Recent progress in the discovery of natural inhibitors against human carboxylesterases. Fitoterapia, 2017, 117, 84-95.
[15]
Redinbo, M.R.; Potter, P.M. Keynote review: Mammalian carboxylesterases: From drug targets to protein therapeutics. Drug Discov. Today, 2005, 10, 313-325.
[16]
Zou, L-W.; Jin, Q.; Wang, D-D.; Qian, Q-K.; Ge, G-B.; Yang, L.; Hao, D-C. Carboxylesterase inhibitors: An update. Curr. Med. Chem., 2018, 25(14), 1627-1649.
[17]
GeneCards®: The Human Gene Database http://www.genecards.org/
[18]
Parker, R.B.; Hu, Z-Y.; Meibohm, B.; Laizure, S.C. Effects of alcohol on human carboxylesterase drug metabolism. Clin. Pharmacokinet., 2015, 54, 627-638.
[19]
Ross, M.K.; Crow, J.A. Human carboxylesterases and their role in xenobiotic and endobiotic metabolism. J. Biochem. Mol. Toxicol., 2007, 21, 187-196.
[20]
Sato, Y.; Miyashita, A.; Iwatsubo, T.; Usui, T. Simultaneous absolute protein quantification of carboxylesterases 1 and 2 in human liver tissue fractions using liquid chromatography-tandem mass spectrometry. Drug Metab. Dispos., 2012, 40, 1389-1396.
[21]
Potter, P.M.; Wolverton, J.S.; Morton, C.L.; Wierdl, M.; Danks, M.K. Cellular localization domains of a rabbit and a human carboxylesterase: Influence on irinotecan (CPT-11) metabolism by the rabbit enzyme. Cancer Res., 1998, 58, 3627-3632.
[22]
Robbi, M.; Beaufay, H. The COOH terminus of several liver carboxylesterases targets these enzymes to the lumen of the endoplasmic reticulum. J. Biol. Chem., 1991, 266, 20498-20503.
[23]
Bencharit, S.; Morton, C.L.; Howard-Williams, E.L.; Danks, M.K.; Potter, P.M.; Redinbo, M.R. Structural insights into CPT-11 activation by mammalian carboxylesterases. Nat. Struct. Biol., 2002, 9, 337-342.
[24]
Bencharit, S.; Morton, C.L.; Xue, Y.; Potter, P.M.; Redinbo, M.R. Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme [Erratum to document cited in CA139:65362]. Nat. Struct. Biol., 2003, 10, 577.
[25]
Bencharit, S.; Morton, C.L.; Hyatt, J.L.; Kuhn, P.; Danks, M.K.; Potter, P.M.; Redinbo, M.R. Crystal structure of human carboxylesterase 1 complexed with the alzheimer’s drug tacrine: From binding promiscuity to selective inhibition. Chem. Biol., 2003, 10, 341-349.
[26]
Fleming, C.D.; Edwards, C.C.; Kirby, S.D.; Maxwell, D.M.; Potter, P.M.; Cerasoli, D.M.; Redinbo, M.R. Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare Agents Soman and Tabun. Biochemistry, 2007, 46, 5063-5071.
[27]
Argikar, U.A.; Potter, P.M.; Hutzler, J.M.; Marathe, P.H. Challenges and opportunities with non-CYP enzymes aldehyde oxidase, carboxylesterase, and UDP-glucuronosyltransferase: Focus on reaction phenotyping and prediction of human clearance. AAPS J., 2016, 18, 1391-1405.
[28]
Xu, J.; Xu, Y.; Xu, Y.; Yin, L.; Zhang, Y.; Xu, J. Global inactivation of carboxylesterase 1 (Ces1/Ces1g) protects against atherosclerosis in Ldlr (-/-) mice. Sci. Rep., 2017, 7, 17845.
[29]
Ross, M.K.; Streit, T.M.; Herring, K.L. Carboxylesterases: Dual roles in lipid and pesticide metabolism. J. Pestic. Sci., 2010, 35, 257-264.
[30]
Hosokawa, M. Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs. Molecules, 2008, 13, 412-431.
[31]
Di, L. The role of drug metabolizing enzymes in clearance. Expert Opin. Drug Metab. Toxicol., 2014, 10, 379-393.
[32]
Na, K.; Lee, E-Y.; Lee, H-J.; Kim, K-Y.; Lee, H.; Jeong, S-K.; Jeong, A-S.; Cho, S.Y.; Kim, S.A.; Song, S.Y.; Kim, K.S.; Cho, S.W.; Kim, H.; Paik, Y-K. Human plasma carboxylesterase 1, a novel serologic biomarker candidate for hepatocellular carcinoma. Proteomics, 2009, 9, 3989-3999.
[33]
Zhen, L.; Rusiniak, M.E.; Swank, R.T. The β-glucuronidase propeptide contains a serpin-related octamer necessary for complex formation with egasyn esterase and for retention within the endoplasmic reticulum. J. Biol. Chem., 1995, 270, 11912-11920.
[34]
Tabata, T.; Katoh, M.; Tokudome, S.; Nakajima, M.; Yokoi, T. Identification of the cytosolic carboxylesterase catalyzing the 5′-deoxy-5-fluorocytidine formation from capecitabine in human liver. Drug Metab. Dispos., 2004, 32, 1103-1110.
[35]
Xu, G.; Zhang, W.; Ma, M.K.; McLeod, H.L. Human carboxylesterase 2 is commonly expressed in tumor tissue and is correlated with activation of irinotecan. Clin. Cancer Res., 2002, 8, 2605-2611.
[36]
Hines, R.N.; Simpson, P.M.; McCarver, D.G. Age-dependent human hepatic carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) postnatal ontogeny. Drug Metab. Dispos., 2016, 44, 959-966.
[37]
Fleming, C.D.; Bencharit, S.; Edwards, C.C.; Hyatt, J.L.; Tsurkan, L.; Bai, F.; Fraga, C.; Morton, C.L.; Howard-Williams, E.L.; Potter, P.M.; Redinbo, M.R. Structural insights into drug processing by human carboxylesterase 1: Tamoxifen, mevastatin, and inhibition by benzil. J. Mol. Biol., 2005, 352, 165-177.
[38]
Human Protein Atlas; https://www.proteinatlas.org/ (Accessed April 3, 2019).
[39]
Wang, X.; Liang, Y.; Liu, L.; Shi, J.; Zhu, H-J. Targeted absolute quantitative proteomics with SILAC internal standards and unlabeled full-length protein calibrators (TAQSI). Rapid Commun. Mass Spectrom., 2016, 30, 553-561.
[40]
Boberg, M.; Vrana, M.; Mehrotra, A.; Pearce, R.E.; Gaedigk, A.; Bhatt, D.K.; Leeder, J.S.; Prasad, B. Age-dependent absolute abundance of hepatic carboxylesterases (CES1 and CES2) by LC-MS/MS proteomics: application to PBPK modeling of oseltamivir in vivo pharmacokinetics in infants. Drug Metab. Dispos., 2017, 45, 216-223.
[41]
Wegler, C.; Gaugaz, F.Z.; Andersson, T.B.; Wisniewski, J.R.; Busch, D.; Groeer, C.; Oswald, S.; Noren, A.; Weiss, F.; Hammer, H.S.; Joos, T.O.; Poetz, O.; Achour, B.; Rostami-Hodjegan, A.; Van De Steeg, E.; Wortelboer, H.M.; Artursson, P. Variability in mass spectrometry-based quantification of clinically relevant drug transporters and drug metabolizing enzymes. Mol. Pharmaceutics., 2017, 14, 3142-3151.
[42]
Sun, A.; Jiang, Y.; Wang, X.; Liu, Q.; Zhong, F.; He, Q.; Guan, W.; Li, H.; Sun, Y.; Shi, L.; Yu, H.; Yang, D.; Xu, Y.; Song, Y.; Tong, W.; Li, D.; Lin, C.; Hao, Y.; Geng, C.; Yun, D.; Zhang, X.; Yuan, X.; Chen, P.; Zhu, Y.; Li, Y.; Liang, S.; Zhao, X.; Liu, S.; He, F. Liverbase: A comprehensive view of human liver biology. J. Proteome Res., 2010, 9, 50-58.
[43]
SIMCYP, Certara, Sheffield, United Kingdom; https://www. certara.com/ (Accessed April 3, 2019).
[44]
Williams, E.T.; Bacon, J.A.; Bender, D.M.; Lowinger, J.J.; Guo, W-K.; Ehsani, M.E.; Wang, X.; Wang, H.; Qian, Y-W.; Ruterbories, K.J.; Wrighton, S.A.; Perkins, E.J. Characterization of the expression and activity of carboxylesterases 1 and 2 from the beagle dog, cynomolgus monkey, and human. Drug Metab. Dispos., 2011, 39, 2305-2313.
[45]
Oda, S.; Fukami, T.; Yokoi, T.; Nakajima, M. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab. Pharmacokinet., 2015, 30, 30-51.
[46]
Bahar, F.G.; Ohura, K.; Ogihara, T.; Imai, T. Species difference of esterase expression and hydrolase activity in plasma. J. Pharm. Sci., 2012, 101, 3979-3988.
[47]
Li, B.; Sedlacek, M.; Manoharan, I.; Boopathy, R.; Duysen, E.G.; Masson, P.; Lockridge, O. Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma. Biochem. Pharmacol., 2005, 70, 1673-1684.
[48]
Morton, C.L.; Iacono, L.; Hyatt, J.L.; Taylor, K.R.; Cheshire, P.J.; Houghton, P.J.; Danks, M.K.; Stewart, C.F.; Potter, P.M. Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice. Cancer Chemother. Pharmacol., 2005, 56, 629-636.
[49]
Soares, E.R. Identification of a new allele of Es-I segregating in an inbred strain of mice. Biochem. Genet., 1979, 17, 577-583.
[50]
Williams, F.M. Clinical significance of esterases in man. Clin. Pharmacokinet., 1985, 10, 392-403.
[51]
Zhu, H-J.; Patrick, K.S.; Yuan, H-J.; Wang, J-S.; Donovan, J.L.; DeVane, C.L.; Malcolm, R.; Johnson, J.A.; Youngblood, G.L.; Sweet, D.H.; Langaee, T.Y.; Markowitz, J.S. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: Clinical significance and molecular basis. Am. J. Hum. Genet., 2008, 82, 1241-1248.
[52]
Ribelles, N.; Lopez-Siles, J.; Sanchez, A.; Gonzalez, E.; Sanchez, M.J.; Carbantes, F.; Sanchez-Rovira, P.; Marquez, A.; Duenas, R.; Sevilla, I.; Alba, E. A carboxylesterase 2 gene polymorphism as predictor of capecitabine on response and time to progression. Curr. Drug Metab., 2008, 9, 336-343.
[53]
Kubo, T.; Kim, S-R.; Sai, K.; Saito, Y.; Nakajima, T.; Matsumoto, K.; Saito, H.; Shirao, K.; Yamamoto, N.; Minami, H.; Ohtsu, A.; Yoshida, T.; Saijo, N.; Ohno, Y.; Ozawa, S.; Sawada, J-I. Functional characterization of three naturally occurring single nucleotide polymorphisms in the CES2 gene encoding carboxylesterase 2 (HCE-2). Drug Metab. Dispos., 2005, 33, 1482-1487.
[54]
Geshi, E.; Kimura, T.; Yoshimura, M.; Suzuki, H.; Koba, S.; Sakai, T.; Saito, T.; Koga, A.; Muramatsu, M.; Katagiri, T. A single nucleotide polymorphism in the carboxylesterase gene is associated with the responsiveness to imidapril medication and the promoter activity. Hypertens. Res., 2005, 28, 719-725.
[55]
Sanghani, S.P.; Sanghani, P.C.; Schiel, M.A.; Bosron, W.F. Human carboxylesterases: an update on CES1, CES2 and CES3. Protein Pept. Lett., 2009, 16, 1207-1214.
[56]
Wang, X.; Rida, N.; Shi, J.; Wu Audrey, H.; Bleske Barry, E.; Zhu, H.J. A comprehensive functional assessment of carboxylesterase 1 nonsynonymous polymorphisms. Drug Metab. Dispos., 2017, 45, 1149-1155.
[57]
Charasson, V.; Bellott, R.; Meynard, D.; Longy, M.; Gorry, P.; Robert, J. Pharmacogenetics of human carboxylesterase 2, an enzyme involved in the activation of irinotecan into SN-38. Clin. Pharmacol. Ther., 2004, 76, 528-535.
[58]
Zhu, W.; Song, L.; Zhang, H.; Matoney, L.; Lecluyse, E.; Yan, B. Dexamethasone differentially regulates expression of carboxylesterase genes in humans and rats. Drug Metab. Dispos., 2000, 28, 186-191.
[59]
Yang, J.; Shi, D.; Yang, D.; Song, X.; Yan, B. Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2. Mol. Pharmacol., 2007, 72, 686-694.
[60]
Zhu, H-J.; Appel, D.I.; Jiang, Y.; Markowitz, J.S. Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab. Dispos., 2009, 37, 1819-1825.
[61]
Yang, J.; Yan, B. Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: Evidence on an involvement of the pregnane X receptor. Toxicol. Sci., 2007, 95, 13-22.
[62]
Staudinger, J.L.; Xu, C.; Cui, Y.J.; Klaassen, C.D. Nuclear receptor-mediated regulation of carboxylesterase expression and activity. Expert Opin. Drug Metab. Toxicol., 2010, 6, 261-271.
[63]
Furihata, T.; Hosokawa, M.; Masuda, M.; Satoh, T.; Chiba, K. Hepatocyte nuclear factor-4α plays pivotal roles in the regulation of mouse carboxylesterase 2 gene transcription in mouse liver. Arch. Biochem. Biophys., 2006, 447, 107-117.
[64]
Cui, J.Y.; Li, C.Y. Regulation of Xenobiotic Metabolism in the Liver. In: Comprehensive Toxicology; 3rd ed.; McQueen, C.A., Ed. Amsterdam: Elservier, 2018.
[65]
Maruichi, T.; Fukami, T.; Nakajima, M.; Yokoi, T. Transcriptional regulation of human carboxylesterase 1A1 by nuclear factor-erythroid 2 related factor 2 (Nrf2). Biochem. Pharmacol., 2010, 79, 288-295.
[66]
Yang, D.; Pearce, R.E.; Wang, X.; Gaedigk, R.; Wan, Y-J.Y.; Yan, B. Human carboxylesterases HCE1 and HCE2: Ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem. Pharmacol., 2009, 77, 238-247.
[67]
Shi, D.; Yang, D.; Prinssen, E.P.; Davies, B.E.; Yan, B. Surge in expression of carboxylesterase 1 during the post-neonatal stage enables a rapid gain of the capacity to activate the anti-influenza prodrug oseltamivir. J. Infect. Dis., 2011, 203, 937-942.
[68]
Chen, Y-T.; Trzoss, L.; Yang, D.; Yan, B. Ontogenic expression of human carboxylesterase-2 and cytochrome P450 3A4 in liver and duodenum: Postnatal surge and organ-dependent regulation. Toxicology, 2015, 330, 55-61.
[69]
Hines, R.N. Age-dependent expression of human drug-metabolizing enzymes. In: Encyclopedia of Drug Metabolism and Interactions; Lyubimov, A.V.; Rodrigues, A.D.; Sinz, M.A., Eds.; New Jersey: John Wiley & Sons, 2012, Vol. 4, pp. 451-483.
[70]
Dalvi Prashant, S.; Singh, A.; Trivedi Hiren, R.; Mistry Suresh, D.; Vyas Bhadresh, R. Adverse drug reaction profile of oseltamivir in children. J. Pharmacol. Pharmacother., 2011, 2, 100-103.
[71]
Vree, T.B.; Dammers, E.; Ulc, I.; Horkovics-Kovats, S.; Ryska, M.; Merkx, I. Differences between lovastatin and simvastatin hydrolysis in healthy male and female volunteers: Gut hydrolysis of lovastatin is twice that of simvastatin. Sci. World J., 2003, 3, 1332-1343.
[72]
Patrick, K.S.; Straughn, A.B.; Minhinnett, R.R.; Yeatts, S.D.; Herrin, A.E.; DeVane, C.L.; Malcolm, R.; Janis, G.C.; Markowitz, J.S. Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clin. Pharmacol. Ther., 2007, 81, 346-353.
[73]
Shi, J.; Wang, X.; Eyler, R.F.; Liang, Y.; Liu, L.; Mueller, B.A.; Zhu, H-J. Association of Oseltamivir Activation with Gender and Carboxylesterase 1 Genetic Polymorphisms. Basic Clin. Pharmacol. Toxicol., 2016, 119, 555-561.
[74]
Robinson, R.P.; Bartlett, J.A.; Bertinato, P.; Bessire, A.J.; Cosgrove, J.; Foley, P.M.; Manion, T.B.; Minich, M.L.; Ramos, B.; Reese, M.R.; Schmahai, T.J.; Swick, A.G.; Tess, D.A.; Vaz, A.; Wolford, A. Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide. Bioorg. Med. Chem. Lett., 2011, 21, 4150-4154.
[75]
McClure, K.F.; Piotrowski, D.W.; Petersen, D.; Wei, L.; Xiao, J.; Londregan, A.T.; Kamlet, A.S.; Dechert-Schmitt, A-M.; Raymer, B.; Ruggeri, R.B.; Canterbury, D.; Limberakis, C.; Liras, S.; DaSilva-Jardine, P.; Dullea, R.G.; Loria, P.M.; Reidich, B.; Salatto, C.T.; Eng, H.; Kimoto, E.; Atkinson, K.; King-Ahmad, A.; Scott, D.; Beaumont, K.; Chabot, J.R.; Bolt, M.W.; Maresca, K.; Dahl, K.; Arakawa, R.; Takano, A.; Halldin, C. Liver-targeted small-molecule inhibitors of proprotein convertase subtilisin/kexin type 9 Synthesis. Angew. Chem. Int. Ed. Engl., 2017, 56, 16218-16222.
[76]
Williams, E.T.; Ehsani, M.E.; Wang, X.; Wang, H.; Qian, Y-W.; Wrighton, S.A.; Perkins, E.J. Effect of buffer components and carrier solvents on in vitro activity of recombinant human carboxylesterases. J. Pharmacol. Toxicol. Methods, 2008, 57, 138-144.
[77]
Imai, T.; Ohura, K. The role of intestinal carboxylesterase in the oral absorption of prodrugs. Curr. Drug Metab., 2010, 11, 793-805.
[78]
Trapa, P.E.; Beaumont, K.; Atkinson, K.; Eng, H.; King-Ahmad, A.; Scott, D.O.; Maurer, T.S.; Di, L. In vitro-In vivo extrapolation of intestinal availability for carboxylesterase substrates using portal vein-cannulated monkey. J. Pharm. Sci., 2017, 106, 898-905.
[79]
Dokoumetzidis, A.; Kalantzi, L.; Fotaki, N. Predictive models for oral drug absorption: From in silico methods to integrated dynamical models. Expert Opin. Drug Metab. Toxicol., 2007, 3, 491-505.
[80]
Yang, J.; Jamei, M.; Yeo, K.R.; Tucker, G.T.; Rostami-Hodjegan, A. Prediction of intestinal first-pass drug metabolism. Curr. Drug Metab., 2007, 8, 676-684.
[81]
Benet, L.Z.; Izumi, T.; Zhang, Y.; Silverman, J.A.; Wacher, V.J. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J. Control. Release, 1999, 62, 25-31.
[82]
Karlsson, F.H.; Bouchene, S.; Hilgendorf, C.; Dolgos, H.; Peters, S.A. Utility of in vitro systems and preclinical data for the prediction of human intestinal first-pass metabolism during drug discovery and preclinical development. Drug Metab. Dispos., 2013, 41, 2033-2046.
[83]
Nishimuta, H.; Sato, K.; Yabuki, M.; Komuro, S. Prediction of the intestinal first-pass metabolism of CYP3A and UGT substrates in humans from in vitro data. Drug Metab. Pharmacokinet., 2011, 26, 592-601.
[84]
Gertz, M.; Harrison, A.; Houston, J.B.; Galetin, A. Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab. Dispos., 2010, 38, 1147-1158.
[85]
Fung, E.N.; Zheng, N.; Arnold, M.E.; Zeng, J. Effective screening approach to select esterase inhibitors used for stabilizing ester-containing prodrugs analyzed by LC-MS/MS. Bioanalysis, 2010, 2, 733-743.
[86]
Zheng, N.; Fung, E.N.; Buzescu, A.; Arnold, M.E.; Zeng, J. Esterase inhibitors as ester-containing drug stabilizers and their hydrolytic products: Potential contributors to the matrix effects on bioanalysis by liquid chromatography/tandem mass spectrometry. Rapid Commun. Mass Spectrom., 2012, 26, 1291-1304.
[87]
Taketani, M.; Shii, M.; Ohura, K.; Ninomiya, S.; Imai, T. Carboxylesterase in the liver and small intestine of experimental animals and human. Life Sci., 2007, 81, 924-932.
[88]
Holenarsipur, V.K.; Gaud, N.; Sinha, J.; Sivaprasad, S.; Bhutani, P.; Subramanian, M.; Singh, S.P.; Arla, R.; Paruchury, S.; Sharma, T.; Marathe, P.; Mandlekar, S. Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: In vitro, in situ intestinal perfusion and portal vein cannulation models. Biopharm. Drug Dispos., 2015, 36(6), 385-397.
[89]
Babusis, D.; Phan, T.K.; Lee, W.A.; Watkins, W.J.; Ray, A.S. Mechanism for effective lymphoid cell and tissue loading following oral administration of nucleotide prodrug GS-7340. Mol. Pharm., 2013, 10, 459-466.
[90]
Pan-Zhou, X-R.; Mayes, B.A.; Rashidzadeh, H.; Gasparac, R.; Smith, S.; Bhadresa, S.; Gupta, K.; Cohen, M.L.; Bu, C.; Good, S.S.; Moussa, A.; Rush, R. Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2′-methylguanosine-5′-monophosphate, in the monkey and formulation optimization for human exposure. Eur. J. Drug Metab. Pharmacokinet., 2016, 41(5), 567-574.
[91]
Grime, K.; Paine, S.W. Species differences in biliary clearance and possible relevance of hepatic uptake and efflux transporters involvement. Drug Metab. Dispos., 2013, 41, 372-378.
[92]
Kimoto, E.; Bi, Y-A.; Kosa, R.E.; Tremaine, L.M.; Varma, M.V.S. Hepatobiliary clearance prediction: species scaling from monkey, dog, and rat, and in vitro-in vivo extrapolation of sandwich-cultured human hepatocytes using 17 drugs. J. Pharm. Sci., 2017, 106, 2795-2804.
[93]
Nishimuta, H.; Houston, J.B.; Galetin, A. Hepatic, intestinal, renal, and plasma hydrolysis of prodrugs in human, cynomolgus monkey, dog, and rat: Implications for in vitro-in vivo extrapolation of clearance of prodrugs. Drug Metab. Dispos., 2014, 42, 1522-1531.
[94]
Umehara, K-I.; Zollinger, M.; Kigondu, E.; Witschi, M.; Juif, C.; Huth, F.; Schiller, H.; Chibale, K.; Camenisch, G. Esterase phenotyping in human liver in vitro: Specificity of carboxylesterase inhibitors. Xenobiotica, 2016, 46, 862-867.
[95]
Bohnert, T.; Patel, A.; Templeton, I.; Chen, Y.; Lu, C.; Lai, G.; Leung, L.; Tse, S.; Einolf, H.J.; Wang, Y-H.; Sinz, M.; Stearns, R.; Walsky, R.; Geng, W.; Sudsakorn, S.; Moore, D.; He, L.; Wahlstrom, J.; Keirns, J.; Narayanan, R.; Lang, D.; Yang, X. Evaluation of a new molecular entity as a victim of metabolic drug-drug interactions-an industry perspective. Drug Metab. Dispos., 2016, 44, 1399-1423.
[96]
Yang, X.; Atkinson, K.; Di, L. Novel cytochrome p450 reaction phenotyping for low-clearance compounds using the hepatocyte relay method. Drug Metab. Dispos., 2016, 44, 460-465.
[97]
Fukami, T.; Kariya, M.; Kurokawa, T.; Iida, A.; Nakajima, M. Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterases. Eur. J. Pharm. Sci., 2015, 78, 47-53.
[98]
Shimizu, M.; Fukami, T.; Nakajima, M.; Yokoi, T. Screening of specific inhibitors for human carboxylesterases or arylacetamide deacetylase. Drug Metab. Dispos., 2014, 42, 1103-1109.
[99]
Bruckmueller, H.; Martin, P.; Kaehler, M.; Haenisch, S.; Ostrowski, M.; Drozdzik, M.; Siegmund, W.; Cascorbi, I.; Oswald, S. Clinically relevant multidrug transporters are regulated by microRNAs along the human intestine. Mol. Pharm., 2017, 14, 2245-2253.
[100]
Mueller, J.; Keiser, M.; Drozdzik, M.; Oswald, S. Expression, regulation and function of intestinal drug transporters: An update. Biol. Chem., 2017, 398, 175-192.
[101]
Berggren, S.; Gall, C.; Wollnitz, N.; Ekelund, M.; Karlbom, U.; Hoogstraate, J.; Schrenk, D.; Lennernaes, H. Gene and protein expression of P-Glycoprotein, MRP1, MRP2, and CYP3A4 in the small and large human intestine. Mol. Pharm., 2007, 4, 252-257.
[102]
Peters, S.A.; Jones, C.R.; Ungell, A-L.; Hatley, O.J.D. Predicting drug extraction in the human gut wall: Assessing contributions from drug metabolizing enzymes and transporter proteins using preclinical models. Clin. Pharmacokinet., 2016, 55, 673-696.
[103]
Strassburg, C.P.; Kneip, S.; Topp, J.; Obermayer-Straub, P.; Barut, A.; Tukey, R.H.; Manns, M.P. Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine. J. Biol. Chem., 2000, 275, 36164-36171.
[104]
Zhang, Q-Y.; Dunbar, D.; Ostrowska, A.; Zeisloft, S.; Yang, J.; Kaminsky, L.S. Characterization of human small intestinal cytochromes P-450. Drug Metab. Dispos., 1999, 27, 804-809.
[105]
Harwood, M.D.; Neuhoff, S.; Carlson, G.L.; Warhurst, G.; Rostami-Hodjegan, A. Absolute abundance and function of intestinal drug transporters: A prerequisite for fully mechanistic in vitro-in vivo extrapolation of oral drug absorption. Biopharm. Drug Dispos., 2013, 34, 2-28.

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