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Central Nervous System Agents in Medicinal Chemistry

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ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

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Research Article

Synthesis and Biological Evaluation of Amino Acid Based Mutual Amide Prodrugs of Phenytoin as Anticonvulsant Agents

Author(s): Sampada Jangam*, Meenakshi Deodhar and Sagar Wankhede

Volume 21, Issue 1, 2021

Published on: 09 November, 2020

Page: [53 - 72] Pages: 20

DOI: 10.2174/1871524920666201109152344

Price: $65

Abstract

Background: Phenytoin (5,5-diphenyl hydantoin) has poor water solubility, which results in incomplete oral availability. Other problems associated with the oral and intramuscular administration of phenytoin are gastric irritation and inflammation at the site of injection.

Objective: The purpose of this study was to synthesize mutual amide prodrugs of phenytoin by using amino acids like glycine, L-tryptophan, L-lysine and taurine.

Methods: These prodrugs were synthesized and characterized by Fourier Transform Infrared (FTIR), Proton nuclear magnetic resonance (1H NMR) and Mass Spectra. Physical and spectral characterization was performed by determination of solubility, maximum wavelength, partition coefficient (log P), ionization constant (pKa), specific (α) and molar rotation (μ), refractive index (n), specific refraction (RS) and molar refraction (RM).

Results: The results obtained from solubility and log P values determination indicated that phenytoin prodrugs can be administered by oral as well as a parenteral route by minimizing the limitations associated with phenytoin. Anticonvulsant activity of prodrugs (4a-4d) was evaluated by using maximal electroshock (MES) and strychnine induced seizure test on albino mice of either sex weighing 25-30 g in which 4b and 4d were found to have significant anticonvulsant activity for MES and strychnine induced seizure test. In vitro enzymatic hydrolysis study of 4b and 4d was performed on liver, intestinal mucosa and plasma sample of male Sprague Dawley rats weighing 280-300 g in which phenytoin was eluted at 10.13 to 10.68 minutes at 220 nm.

Conclusion: The results obtained from the present work showed that amino acid-based mutual prodrug strategy can be a promising method to increase the solubility and anticonvulsant activity of phenytoin for the development of anticonvulsant agents.

Keywords: Phenytoin, amino acid, mutual prodrug, solubility, anticonvulsant, hydrolysis.

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[1]
Elizabeth CM. de Lange. The mastermind approach to CNS drug therapy: Translational prediction of human brain distribution, target site kinetics, and therapeutic effects. Fluids Barriers CNS 2013; 10: 1-16.
[2]
De Caro V, Giandalia G, Siragusa MG, et al. N-valproyl-L-tryptophan for CNS-targeting: Synthesis, characterization and efficacy in vitro studies of a new potential antiepileptic drug. Med Chem 2011; 7(1): 9-17.
[http://dx.doi.org/10.2174/157340611794072733] [PMID: 21235514]
[3]
McNamara JO. Pharmacotherapy of the epilepsies Lazo, JS; Parker, KL Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw Hill 2006; pp. 521-48.
[4]
Pevarello P, Bonsignori A, Caccia C, et al. Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsants. Bioorg Med Chem Lett 1999; 9(17): 2521-4.
[http://dx.doi.org/10.1016/S0960-894X(99)00415-1] [PMID: 10498200]
[5]
Villetti G, Bregola G, Bassani F, et al. Preclinical evaluation of CHF3381 as a novel antiepileptic agent. Neuropharmacology 2001; 40(7): 866-78.
[http://dx.doi.org/10.1016/S0028-3908(01)00026-0] [PMID: 11378157]
[6]
White HS. Preclinical development of antiepileptic drugs: Past, present, and future directions. Epilepsia 2003; 44(Suppl. 7): 2-8.
[http://dx.doi.org/10.1046/j.1528-1157.44.s7.10.x] [PMID: 12919332]
[7]
Bigge CF, Boxer PA. Neuronal Cell Death and Strategies for Neuroprotection Annual Reports on Medicinal Chemistry. Ann Arbor, Michigan: Academic Press 1994; pp. 13-22.
[8]
Wong MG, Defina JA, Andrews PR. Conformational analysis of clinically active anticonvulsant drugs. J Med Chem 1986; 29(4): 562-72.
[http://dx.doi.org/10.1021/jm00154a022] [PMID: 3959032]
[9]
Stella VJ, Martodihardjo S, Rao VM. Aqueous solubility and dissolution rate does not adequately predict in vivo performance: A probe utilizing some N-acyloxymethyl phenytoin prodrugs. J Pharm Sci 1999; 88(8): 775-9.
[http://dx.doi.org/10.1021/js980489i] [PMID: 10430541]
[10]
Bosch J, Roca T, Domènech J, Suriol M. Synthesis of water-soluble phenytoin prodrugs. Bioorg Med Chem Lett 1999; 9(13): 1859-62.
[http://dx.doi.org/10.1016/S0960-894X(99)00294-2] [PMID: 10406655]
[11]
Foye WO. Foye’s principles of medicinal chemistry. 6th ed. New York: Lippincott Williams & Wilkins 2008.
[12]
Redasani VK, Bari SB. Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol. Eur J Med Chem 2012; 56: 134-8.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.030] [PMID: 22982120]
[13]
Rasheed A, Kumar CK, Mishra A. Synthesis, hydrolysis studies and phamacodynamic profiles of amide prodrugs of dexibuprofen with amino acids. J Enzyme Inhib Med Chem 2011; 26(5): 688-95.
[http://dx.doi.org/10.3109/14756366.2010.548327] [PMID: 21250819]
[14]
Rooseboom M, Commandeur JN, Vermeulen NP. Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol Rev 2004; 56(1): 53-102.
[http://dx.doi.org/10.1124/pr.56.1.3] [PMID: 15001663]
[15]
Nakamura K, Masuda Y, Nakatsuji K, Hiroka T. Comparative studies on the distribution and metabolic fate of diphenylhydantoin and 3-ethoxycarbonyldiphenylhydantoin (P-6127) after chronic administrations to dogs and cats. Naunyn Schmiedebergs Arch Pharmakol Exp Pathol 1966; 254: 406-17.
[http://dx.doi.org/10.1007/BF00539915]
[16]
Cloyd J, Hauser W, Towne A, et al. Epidemiological and medical aspects of epilepsy in the elderly. Epilepsy Res 2006; 68(Suppl. 1): S39-48.
[http://dx.doi.org/10.1016/j.eplepsyres.2005.07.016] [PMID: 16384689]
[17]
Bundgaard H, Johansen M. Pro-drugs as drug delivery systems VIII. Bioreversible derivatization of hydantoins by N-hydroxy-methylation. Int J Pharm 1980; 5: 67-77.
[http://dx.doi.org/10.1016/0378-5173(80)90051-4]
[18]
Varia SA, Stella VJ. Phenytoin prodrugs V: In vivo evaluation of some water-soluble phenytoin prodrugs in dogs. J Pharm Sci 1984; 73(8): 1080-7.
[http://dx.doi.org/10.1002/jps.2600730814] [PMID: 6548519]
[19]
Yamaoka Y, Roberts RD, Stella VJ. Low-melting phenytoin prodrugs as alternative oral delivery modes for phenytoin: A model for other high-melting sparingly water-soluble drugs. J Pharm Sci 1983; 72(4): 400-5.
[http://dx.doi.org/10.1002/jps.2600720420] [PMID: 6864479]
[20]
Shek E, Murakami T, Nath C, Pop E, Bodor NS. Improved anticonvulsant activity of phenytoin by a redox brain delivery system. III: Brain uptake and pharmacological effects. J Pharm Sci 1989; 78(10): 837-43.
[http://dx.doi.org/10.1002/jps.2600781012] [PMID: 2600790]
[21]
Pop E, Shek E, Murakami T, Bodor NS. Improved anticonvulsant activity of phenytoin by a redox brain delivery system I: Synthesis and some properties of the dihydropyridine derivatives. J Pharm Sci 1989; 78(8): 609-16.
[http://dx.doi.org/10.1002/jps.2600780802] [PMID: 2778665]
[22]
Boucher BA, Bombassaro AM, Rasmussen SN, Watridge CB, Achari R, Turlapaty P. Phenytoin prodrug 3-phosphoryloxymethyl phenytoin (ACC-9653): Pharmacokinetics in patients following intravenous and intramuscular administration. J Pharm Sci 1989; 78(11): 929-32.
[http://dx.doi.org/10.1002/jps.2600781110] [PMID: 2621577]
[23]
Ramsay RE, Wilder BJ, Uthman BM, et al. Intramuscular fosphenytoin (Cerebyx) in patients requiring a loading dose of phenytoin. Epilepsy Res 1997; 28(3): 181-7.
[http://dx.doi.org/10.1016/S0920-1211(97)00054-5] [PMID: 9332883]
[24]
Dal Pozzo A, Acquasaliente M. New highly water-soluble phenytoin prodrugs. Int J Pharm 1992; 81: 263-5.
[http://dx.doi.org/10.1016/0378-5173(92)90018-W]
[25]
Scriba GK. Phenytoin-lipid conjugates: Chemical, plasma esterase-mediated, and pancreatic lipase-mediated hydrolysis in vitro. Pharm Res 1993; 10(8): 1181-6.
[http://dx.doi.org/10.1023/A:1018972419482] [PMID: 8415405]
[26]
Scriba GK, Lambert DM, Poupaert JH. Bioavailability of phenytoin following oral administration of phenytoin-lipid conjugates to rats. J Pharm Pharmacol 1995; 47(11): 945-8.
[http://dx.doi.org/10.1111/j.2042-7158.1995.tb03275.x] [PMID: 8708990]
[27]
Redden PR, Melanson RL, Douglas JA, Dick AJ. Acyloxymethyl acidic drug derivatives: In vitro hydrolytic reactivity. Int J Pharm 1999; 180(2): 151-60.
[http://dx.doi.org/10.1016/S0378-5173(98)00372-X] [PMID: 10370185]
[28]
Dyla T, Zygmunt M, Macia DJ. Handzlik, Bednarski, M.; Filipek, B.; Kieć-Kononowicz, K. Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives. Eur J Med Chem 2004; 39: 1013-27.
[http://dx.doi.org/10.1016/j.ejmech.2004.05.008]
[29]
Lambert DM, Masereel B, Gallez B, Geurts M, Scriba GK. Bioavailability and anticonvulsant activity of 2-cyanoguanidino-phenytoin, a structural analogue of phenytoin. J Pharm Sci 1996; 85(10): 1077-81.
[http://dx.doi.org/10.1021/js960093b] [PMID: 8897274]
[30]
Scriba GK, Lambert DM. Synthesis and anticonvulsant activity of N-benzyloxycarbonyl-amino acid prodrugs of phenytoin. J Pharm Pharmacol 1999; 51(5): 549-53.
[http://dx.doi.org/10.1211/0022357991772835] [PMID: 10411214]
[31]
Deodhar M, Sable P, Bhosale A, Juvale K, Dumbare R, Sakpal P. Synthesis and evaluation of phenytoin derivatives as anticonvulsant agents. Turk J Chem 2009; 33: 367-73.
[32]
Chang YF, Gao XM. L-lysine is a barbiturate-like anticonvulsant and modulator of the benzodiazepine receptor. Neurochem Res 1995; 20(8): 931-7.
[http://dx.doi.org/10.1007/BF00970739] [PMID: 8587651]
[33]
Chang YF, Hargest V, Chen JS. Modulation of benzodiazepine by lysine and pipecolic acid on pentylenetetrazol-induced seizures. Life Sci 1988; 43(15): 1177-88.
[http://dx.doi.org/10.1016/0024-3205(88)90207-X] [PMID: 2845210]
[34]
Chang YF, Myslinski NR. Effects of L-lysine and its metabolites on pentylenetetrazol-induced seizures. Neurosci Lett 1985; 59(1): 79-84.
[http://dx.doi.org/10.1016/0304-3940(85)90218-6] [PMID: 2995882]
[35]
Sandyk R. L-tryptophan in neuropsychiatric disorders: A review. Int J Neurosci 1992; 67(1-4): 127-44.
[http://dx.doi.org/10.3109/00207459208994781] [PMID: 1305630]
[36]
Andersen L, Sundman LO, Lindén IB, Kontro P, Oja SS. Synthesis and anticonvulsant properties of some 2-aminoethanesulfonic acid (taurine) derivatives. J Pharm Sci 1984; 73(1): 106-8.
[http://dx.doi.org/10.1002/jps.2600730128] [PMID: 6694063]
[37]
Oja SS, Saransaari P. Taurine as osmoregulator and neuromodulator in the brain. Metab Brain Dis 1996; 11(2): 153-64.
[http://dx.doi.org/10.1007/BF02069502] [PMID: 8776717]
[38]
Wu JY, Prentice H. Role of taurine in the central nervous system. J Biomed Sci 2010; 17(Suppl. 1): S1.
[http://dx.doi.org/10.1186/1423-0127-17-S1-S1] [PMID: 20804583]
[39]
Norberg S, Powell TL, Jansson T. Intrauterine growth restriction is associated with a reduced activity of placental taurine transporters. Pediatr Res 1998; 44(2): 233-8.
[http://dx.doi.org/10.1203/00006450-199808000-00016] [PMID: 9702920]
[40]
Barbeau A. The brain, the heart and taurine. Can J Neurol Sci 1975; 2(4): 343-6.
[http://dx.doi.org/10.1017/S0317167100020461] [PMID: 1104123]
[41]
Ashihara M, Takuya O, Nishimura T, Sakai M, Nagatsu I. Immunohistochemical study of the human olfactory system. Nippon Jibiinkoka Gakkai Kaiho 1992; 95(6): 851-9.
[http://dx.doi.org/10.3950/jibiinkoka.95.851] [PMID: 1353114]
[42]
Chapman GE, Greenwood CE. Taurine in nutrition and brain development. Nutr Res 1988; 8: 955-68.
[http://dx.doi.org/10.1016/S0271-5317(88)80135-0]
[43]
Oja SS, Lehtinen I, Lähdesmäki P. Taurine transport rates between plasma and tissues in adult and 7-day-old mice. Q J Exp Physiol Cogn Med Sci 1976; 61(2): 133-43.
[http://dx.doi.org/10.1113/expphysiol.1976.sp002344] [PMID: 1047457]
[44]
Geurts M, Poupaert JH, Scriba GK, Lambert DMNN. -(benzyloxycarbonyl)glycine esters and amides as new anticonvulsants. J Med Chem 1998; 41(1): 24-30.
[http://dx.doi.org/10.1021/jm970086f] [PMID: 9438018]
[45]
Toth E, Lajtha A, Sarhan S, Seiler N. Anticonvulsant effects of some inhibitory neurotransmitter amino acids. Neurochem Res 1983; 8(3): 291-302.
[http://dx.doi.org/10.1007/BF00965719] [PMID: 6134243]
[46]
Lapin IP. Antagonism of L-glycine to seizures induced by L-kynurenine, quinolinic acid and strychnine in mice. Eur J Pharmacol 1981; 71(4): 495-8.
[http://dx.doi.org/10.1016/0014-2999(81)90195-3] [PMID: 7250201]
[47]
Seiler N, Sarhan S. Synergistic anticonvulsant effects of GABA-T inhibitors and glycine. Naunyn Schmiedebergs Arch Pharmacol 1984; 326(1): 49-57.
[http://dx.doi.org/10.1007/BF00518778] [PMID: 6472485]
[48]
Seiler N, Sarhan S. Synergistic anticonvulsant effects of a GABA agonist and glycine. Gen Pharmacol 1984; 15(4): 367-9.
[http://dx.doi.org/10.1016/0306-3623(84)90018-1] [PMID: 6489732]
[49]
Wood JD, Watson WJ, Stacey NE. A comparative study of Hyperbaric Oxygen induced and drug‐induced convulsions with particular reference to γ‐aminobutyric acid metabolism. J Neurochem 1966; 13: 361-70.
[http://dx.doi.org/10.1111/j.1471-4159.1966.tb06811.x]
[50]
Halsey MJ, Little HJ, Wardley-Smith B. Systemically administered glycine protects against strychnine convulsions, but not the behavioural effects of high pressure, in mice. J Physiol 1989; 408: 431-41.
[http://dx.doi.org/10.1113/jphysiol.1989.sp017468] [PMID: 2778736]
[51]
Liu Z, Seiler N, Marescaux C, Depaulis A, Vergnes M. Potentiation of γ-vinyl GABA (vigabatrin) effects by glycine. Eur J Pharmacol 1990; 182(1): 109-15.
[http://dx.doi.org/10.1016/0014-2999(90)90498-U] [PMID: 2119308]
[52]
Tanino T, Ogiso T, Iwaki M, Tanabe G, Muraoka O. Enhancement of oral bioavailability of phenytoin by esterification, and in vitro hydrolytic characteristics of prodrugs. Int J Pharm 1998; 163: 91-102.
[http://dx.doi.org/10.1016/S0378-5173(97)00374-8]
[53]
Mishra A, Veerasamy R, Jain PK, Dixit VK, Agrawal RK. Synthesis, characterization and pharmacological evaluation of amide prodrugs of flurbiprofen. J Braz Chem Soc 2008; 19: 89-100.
[http://dx.doi.org/10.1590/S0103-50532008000100014]
[54]
Jones SM, Urch JE, Kaiser M, et al. Analogues of thiolactomycin as potential antimalarial agents. J Med Chem 2005; 48(19): 5932-41.
[http://dx.doi.org/10.1021/jm049067d] [PMID: 16161997]
[55]
Perreux L, Loupy A, Delmotte M. Microwave effects in solvent-free esters aminolysis. Tetrahedron 2003; 59: 2185-9.
[http://dx.doi.org/10.1016/S0040-4020(03)00151-0]
[56]
Indian Pharmacopoeia; The Indian pharmacopoeia commission.. Central Indian Pharmacopoeia Laboratory, Ministry of Health and Family Welfare, Govt of India, Sector. 2007.
[57]
Mishra A, Veerasamy R, Jain PK, Dixit VK, Agrawal RK. Synthesis, characterization and pharmacological evaluation of amide prodrugs of ketorolac. Eur J Med Chem 2008; 43(11): 2464-72.
[http://dx.doi.org/10.1016/j.ejmech.2007.09.011] [PMID: 17967497]
[58]
Beckett A, Stenlake J. Practical Pharmaceutical Chemistry-Part Two. 4th ed. CBS publications : New Delhi 2005.
[59]
De Bruijn J, Busser F, Seinen W, Hermens J. Determination of octanol/water partition coefficients for hydrophobic organic chemicals with the “slow‐stirring” method. Environ Toxicol Chem 1989; 8: 499-512.
[http://dx.doi.org/10.1002/etc.5620080607]
[60]
Albert A. The determination of ionization constants: A laboratory manual. 3rd ed. Springer Science & Business Media 2012.
[61]
More HN, Hajare AA. Practical physical pharmacy. 1st ed. India: Career Publication 2007.
[62]
Kim CB, Su CB. Measurement of the refractive index of liquids at 1.3 and 1.5 micron using a fibre optic Fresnel ratio meter. Meas Sci Technol 2004; 15: 1683-6.
[http://dx.doi.org/10.1088/0957-0233/15/9/002]
[63]
Vogel H. Drug discovery and evaluation pharmacological assays.2nd ed. Springer publication: Berlin 2002.
[http://dx.doi.org/10.1007/3-540-29837-1]
[64]
Achliya GS, Wadodkar SG, Dorle AK. Evaluation of sedative and anticonvulsant activities of Unmadnashak Ghrita. J Ethnopharmacol 2004; 94(1): 77-83.
[http://dx.doi.org/10.1016/j.jep.2004.04.020] [PMID: 15261966]
[65]
Swinyard EA, Sofia RD, Kupferberg HJ. Comparative anticonvulsant activity and neurotoxicity of felbamate and four prototype antiepileptic drugs in mice and rats. Epilepsia 1986; 27(1): 27-34.
[http://dx.doi.org/10.1111/j.1528-1157.1986.tb03497.x] [PMID: 3004930]
[66]
Bum EN, Schmutz M, Meyer C, et al. Anticonvulsant properties of the methanolic extract of Cyperus articulatus (Cyperaceae). J Ethnopharmacol 2001; 76(2): 145-50.
[http://dx.doi.org/10.1016/S0378-8741(01)00192-1] [PMID: 11390127]
[67]
Najlah M, Freeman S, Attwood D, D’Emanuele A. In vitro evaluation of dendrimer prodrugs for oral drug delivery. Int J Pharm 2007; 336(1): 183-90.
[http://dx.doi.org/10.1016/j.ijpharm.2006.11.047] [PMID: 17188439]
[68]
Dittert LW, Caldwell HC, Ellison T, Irwin GM, Rivard DE, Swintosky JV. Carbonate ester prodrugs of salicylic acid. Synthesis, solubility characteristics, in vitro enzymatic hydrolysis rates, and blood levels of total salicylate following oral administration to dogs. J Pharm Sci 1968; 57(5): 828-31.
[http://dx.doi.org/10.1002/jps.2600570523] [PMID: 5657544]
[69]
Yang C, Gao H, Mitra AK. Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir. J Pharm Sci 2001; 90(5): 617-24.
[http://dx.doi.org/10.1002/1520-6017(200105)90:5<617:AID-JPS1018>3.0.CO;2-5] [PMID: 11288106]
[70]
Smith MB, March J. Advanced Organic Chemistry. 5th ed. New York: John Wiley & Sons, Inc. 2001.
[71]
Isidro-Llobet A, Alvarez M, Albericio F. Amino acid-protecting groups. Chem Rev 2009; 109(6): 2455-504.
[http://dx.doi.org/10.1021/cr800323s] [PMID: 19364121]
[72]
Waldmann H, Kunz H. The allyl group as mildly and selectively removable carboxy-protecting group for the synthesis of labile O-glycopeptides. Ann Chem 1983; 10: 1712-25.
[73]
Jensen KJ, Alsina J, Songster MF, Vágner J, Albericio F, Barany G. Backbone Amide Linker (BAL) strategy for solid-phase synthesis of C-Terminal-Modified and Cyclic Peptides. J Am Chem Soc 1998; 120: 5441-52.
[http://dx.doi.org/10.1021/ja974116f]
[74]
Thieriet N, Guibé F, Albericio F. Solid-phase peptide synthesis in the reverse (N --> C) direction. Org Lett 2000; 2(13): 1815-7.
[http://dx.doi.org/10.1021/ol0058341] [PMID: 10891165]
[75]
Visintin C, Aliev AE, Riddall D, et al. Membrane receptor probes: solid-phase synthesis of biotin-Asp-PEG-arvanil derivatives. Org Lett 2005; 7(9): 1699-702.
[http://dx.doi.org/10.1021/ol0502578] [PMID: 15844884]
[76]
Albericio F. Orthogonal protecting groups for N(α)-amino and C-terminal carboxyl functions in solid-phase peptide synthesis. Biopolymers 2000; 55(2): 123-39.
[http://dx.doi.org/10.1002/1097-0282(2000)55:2<123:AID-BIP30>3.0.CO;2-F] [PMID: 11074410]
[77]
Hosangadi BD, Dave RH. An efficient general method for esterification of aromatic carboxylic acids. Tetrahedron Lett 1996; 37: 6375-8.
[http://dx.doi.org/10.1016/0040-4039(96)01351-2]
[78]
Clayden J, Greeves N, Warren S, Wothers P. Organic Chemistry. 1st ed. New York: Oxford University Press 2004.
[79]
Ghosh S. Advanced General Organic Chemistry. 2nd ed. Kolkata, India: New Central Book Agency 2007.
[80]
Block J, Beale J. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry. 11th ed. New York: Lippincott Williams and Wilkins 2004.
[81]
Drayer DE. Pharmacologically active drug metabolites: therapeutic and toxic activities, plasma and urine data in man, accumulation in renal failure. Clin Pharmacokinet 1976; 1(6): 426-43.
[http://dx.doi.org/10.2165/00003088-197601060-00003] [PMID: 799549]
[82]
Drayer DE. Pharmacologically active metabolites of drugs and other foreign compounds. Clinical, pharmacological, therapeutic and toxicological considerations. Drugs 1982; 24(6): 519-42.
[http://dx.doi.org/10.2165/00003495-198224060-00003] [PMID: 6759093]
[83]
Verbeeck RK. Blood microdialysis in pharmacokinetic and drug metabolism studies. Adv Drug Deliv Rev 2000; 45(2-3): 217-28.
[http://dx.doi.org/10.1016/S0169-409X(00)00110-1] [PMID: 11108975]

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