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Current Drug Metabolism

Author(s): Joe Miantezila Basilua*, Olivier Sawoo, Irène Mangin, Flore Dossou-Yovo, Aline Boussard, Lucie Chevillard, Gaston T. Lutete, Bruno Eto, Gilles Peytavin and Philippe Pochart

DOI: 10.2174/1389200220666191023105609

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Higher Atazanavir Plasma Exposure in Rats is Associated with Gut Microbiota Changes Induced by Cotrimoxazole

Page: [898 - 906] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Background: Cotrimoxazole (TMP-SMX) is concomitantly used as a primary prophylaxis of opportunistic infections with antiretroviral agents, such as Atazanavir (ATV). Results from an ex vivo study showed changes in intestinal absorption of ATV when rats were pretreated with TMP-SMX. The objective of this in vivo study is to determine the effect of TMP-SMX on the pharmacokinetics of ATV in rats. We also studied changes in gut microbiota induced by TMP-SMX.

Methods: We used the non-compartment analysis to compare the pharmacokinetics of ATV in a parallel group of rats treated with a low or therapeutic dose of TMP-SMX for nine days to untreated control rats. Gut microbiota was characterized using qPCR and High Throughput Sequencing of 16S rDNA.

Results: Rats treated with TMP-SMX showed a much broader exposure to ATV compared to the control group (AUC0-8h (ng.mL-1.h), 25975.9±4048.7 versus 2587.6±546.9, p=0.001). The main observation regarding the gut microbiota was a lower proportion of enterobacteria related to the administration of TMP-SMX. Moreover, the Total Gastrointestinal Transit Time (TGTT) was longer in the TMP-SMX treated group.

Conclusion: Concomitant administration of TMP-SMX and ATV significantly increased ATV exposure in rats. This increase could be the result of a prolonged TGTT leading to an increase in the intestinal residence time of ATV favoring its absorption. Gut microbiota changes induced by TMP-SMX could be at the origin of this prolonged TGTT. If demonstrated in humans, this potential interaction could be accompanied by an increase in the adverse effects of ATV.

Keywords: Cotrimoxazole, atazanavir, gut microbiota, gastrointestinal motility, intestinal absorption, enterohepatic circulation, plasma exposure.

Graphical Abstract

[1]
Perloff, E.S.; Duan, S.X.; Skolnik, P.R.; Greenblatt, D.J.; Von Moltke, L.L. Atazanavir: Effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab. Dispos., 2005, 33(6), 764-770.
[http://dx.doi.org/10.1124/dmd.104.002931] [PMID: 15764714]
[2]
Piliero, P.J. Atazanavir: A novel once-daily protease inhibitor. Drugs Today (Barc), 2004, 40(11), 901-912.
[http://dx.doi.org/10.1358/dot.2004.40.11.872579] [PMID: 15645003]
[3]
Dossou-Yovo, F.; Mamadou, G.; Soudy, I.D.; Limas-Nzouzi, N.; Miantezila, J.; Desjeux, J-F.; Eto, B. Metronidazole or Cotrimoxazole therapy is associated with a decrease in intestinal bioavailability of common antiretroviral drugs. PLoS One, 2014, 9(2)e89943
[http://dx.doi.org/10.1371/journal.pone.0089943] [PMID: 24587140]
[4]
Pélissier, M-A.; Vasquez, N.; Balamurugan, R.; Pereira, E.; Dossou-Yovo, F.; Suau, A.; Pochart, P.; Magne, F. Metronidazole effects on microbiota and mucus layer thickness in the rat gut. FEMS Microbiol. Ecol., 2010, 73(3), 601-610.
[http://dx.doi.org/10.1111/j.1574-6941.2010.00916.x] [PMID: 20579100]
[5]
Mangin, I.; Dossou-Yovo, F.; Lévêque, C.; Dessoy, M-V.; Sawoo, O.; Suau, A.; Pochart, P. Oral administration of viable Bifidobacterium pseudolongum strain Patronus modified colonic microbiota and increased mucus layer thickness in rat. FEMS Microbiol. Ecol., 2018, 94(11), 4.
[http://dx.doi.org/10.1093/femsec/fiy177] [PMID: 30184128]
[6]
Wing, L.M.; Miners, J.O. Cotrimoxazole as an inhibitor of oxidative drug metabolism: Effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition. Br. J. Clin. Pharmacol., 1985, 20(5), 482-485.
[http://dx.doi.org/10.1111/j.1365-2125.1985.tb05102.x] [PMID: 3878154]
[7]
Wen, X.; Wang, J-S.; Backman, J.T.; Laitila, J.; Neuvonen, P.J. Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively. Drug Metab. Dispos., 2002, 30(6), 631-635.
[http://dx.doi.org/10.1124/dmd.30.6.631] [PMID: 12019187]
[8]
Kimura, T.; Higaki, K. Gastrointestinal transit and drug absorption. Biol. Pharm. Bull., 2002, 25(2), 149-164.
[http://dx.doi.org/10.1248/bpb.25.149] [PMID: 11853157]
[9]
McGivern, R.F.; Henschel, D.; Hutcheson, M.; Pangburn, T. Sex difference in daily water consumption of rats: Effect of housing and hormones. Physiol. Behav., 1996, 59(4-5), 653-658.
[http://dx.doi.org/10.1016/0031-9384(95)02017-9] [PMID: 8778848]
[10]
Gueye, P.N.; Borron, S.W.; Risède, P.; Monier, C.; Buneaux, F.; Debray, M.; Baud, F.J. Buprenorphine and midazolam act in combination to depress respiration in rats. Toxicol. Sci., 2002, 65(1), 107-114.
[http://dx.doi.org/10.1093/toxsci/65.1.107] [PMID: 11752690]
[11]
Tomilo, D.L.; Smith, P.F.; Ogundele, A.B.; Difrancesco, R.; Berenson, C.S.; Eberhardt, E.; Bednarczyk, E.; Morse, G.D. Inhibition of atazanavir oral absorption by lansoprazole gastric acid suppression in healthy volunteers. Pharmacotherapy, 2006, 26(3), 341-346.
[http://dx.doi.org/10.1592/phco.26.3.341] [PMID: 16503713]
[12]
McConnell, E.L.; Basit, A.W.; Murdan, S. Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in vivo experiments. J. Pharm. Pharmacol., 2008, 60(1), 63-70.
[http://dx.doi.org/10.1211/jpp.60.1.0008] [PMID: 18088506]
[13]
Boussard, A.; Cordella, C.B.Y.; Rakotozafy, L.; Moulin, G.; Buche, F.; Potus, J.; Nicolas, J. Use of chemometric tools to estimate the effects of the addition of yeast, glucose-oxidase, soybean or horse bean flours to wheat flour on biochemical bread dough characteristics. Chemom. Intell. Lab. Syst., 2012, 113, 68-77.
[http://dx.doi.org/10.1016/j.chemolab.2012.01.006]
[14]
Dey, S.; Subhasis Patro, S.; Suresh Babu, N.; Murthy, P.N.; Panda, S.K. Development and validation of a stability-indicating RP-HPLC method for estimation of atazanavir sulfate in bulk. J. Pharm. Anal., 2017, 7(2), 134-140.
[http://dx.doi.org/10.1016/j.jpha.2013.12.002] [PMID: 29404029]
[15]
Jung, B.H.; Rezk, N.L.; Bridges, A.S.; Corbett, A.H.; Kashuba, A.D.M. Simultaneous determination of 17 antiretroviral drugs in human plasma for quantitative analysis with liquid chromatography-tandem mass spectrometry. Biomed. Chromatogr., 2007, 21(10), 1095-1104.
[http://dx.doi.org/10.1002/bmc.865] [PMID: 17582235]
[16]
Godon, J.J.; Zumstein, E.; Dabert, P.; Habouzit, F.; Moletta, R. Molecular microbial diversity of an anaerobic digestor as determined by small-subunit rDNA sequence analysis. Appl. Environ. Microbiol., 1997, 63(7), 2802-2813.
[PMID: 9212428]
[17]
Mangin, I.; Suau, A.; Magne, F.; Garrido, D.; Gotteland, M.; Neut, C.; Pochart, P. Characterization of human intestinal bifidobacteria using competitive PCR and PCR-TTGE. FEMS Microbiol. Ecol., 2006, 55(1), 28-37.
[http://dx.doi.org/10.1111/j.1574-6941.2005.00005.x] [PMID: 16420612]
[18]
Rausch, P.; Rühlemann, M.; Hermes, B.M.; Doms, S.; Dagan, T.; Dierking, K.; Domin, H.; Fraune, S.; von Frieling, J.; Hentschel, U.; Heinsen, F.A.; Höppner, M.; Jahn, M.T.; Jaspers, C.; Kissoyan, K.A.B.; Langfeldt, D.; Rehman, A.; Reusch, T.B.H.; Roeder, T.; Schmitz, R.A.; Schulenburg, H.; Soluch, R.; Sommer, F.; Stukenbrock, E.; Weiland-Bräuer, N.; Rosenstiel, P.; Franke, A.; Bosch, T.; Baines, J.F. Comparative analysis of amplicon and metagenomic sequencing methods reveals key features in the evolution of animal metaorganisms. Microbiome, 2019, 7(1), 133.
[http://dx.doi.org/10.1186/s40168-019-0743-1] [PMID: 31521200]
[19]
Escudié, F.; Auer, L.; Bernard, M.; Mariadassou, M.; Cauquil, L.; Vidal, K.; Maman, S.; Hernandez-Raquet, G.; Combes, S.; Pascal, G. FROGS: Find, rapidly, OTUs with galaxy solution. Bioinformatics, 2018, 34(8), 1287-1294.
[http://dx.doi.org/10.1093/bioinformatics/btx791] [PMID: 29228191]
[20]
Gouy, M.; Guindon, S.; Gascuel, O. SeaView version 4: A multiplatform graphical user interface for sequence alignment and phylogenetic tree building. Mol. Biol. Evol., 2010, 27(2), 221-224.
[http://dx.doi.org/10.1093/molbev/msp259] [PMID: 19854763]
[21]
Guindon, S.; Dufayard, J-F.; Lefort, V.; Anisimova, M.; Hordijk, W.; Gascuel, O. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst. Biol., 2010, 59(3), 307-321.
[http://dx.doi.org/10.1093/sysbio/syq010] [PMID: 20525638]
[22]
Segata, N.; Izard, J.; Waldron, L.; Gevers, D.; Miropolsky, L.; Garrett, W.S.; Huttenhower, C. Metagenomic biomarker discovery and explanation. Genome Biol., 2011, 12(6), R60.
[http://dx.doi.org/10.1186/gb-2011-12-6-r60] [PMID: 21702898]
[23]
Ge, X.; Ding, C.; Zhao, W.; Xu, L.; Tian, H.; Gong, J.; Zhu, M.; Li, J.; Li, N. Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility. J. Transl. Med., 2017, 15(1), 13.
[http://dx.doi.org/10.1186/s12967-016-1105-4] [PMID: 28086815]
[24]
Haruta, S.; Iwasaki, N.; Ogawara, K.; Higaki, K.; Kimura, T. Absorption behavior of orally administered drugs in rats treated with propantheline. J. Pharm. Sci., 1998, 87(9), 1081-1085.
[http://dx.doi.org/10.1021/js980117+] [PMID: 9724558]
[25]
Yano, J.M.; Yu, K.; Donaldson, G.P.; Shastri, G.G.; Ann, P.; Ma, L.; Nagler, C.R.; Ismagilov, R.F.; Mazmanian, S.K.; Hsiao, E.Y. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 2015, 161(2), 264-276.
[http://dx.doi.org/10.1016/j.cell.2015.02.047] [PMID: 25860609]
[26]
Roshchina, V.V. New trends and perspectives in the evolution of neurotransmitters in microbial, plant, and animal cells. Adv. Exp. Med. Biol., 2016, 874, 25-77.
[http://dx.doi.org/10.1007/978-3-319-20215-0_2] [PMID: 26589213]
[27]
Esmaili, A.; Nazir, S.F.; Borthakur, A.; Yu, D.; Turner, J.R.; Saksena, S.; Singla, A.; Hecht, G.A.; Alrefai, W.A.; Gill, R.K. Enteropathogenic Escherichia coli infection inhibits intestinal serotonin transporter function and expression. Gastroenterology, 2009, 137(6), 2074-2083.
[http://dx.doi.org/10.1053/j.gastro.2009.09.002] [PMID: 19747920]
[28]
Marathe, P.H.; Wen, Y.; Norton, J.; Greene, D.S.; Barbhaiya, R.H.; Wilding, I.R. Effect of altered gastric emptying and gastrointestinal motility on metformin absorption. Br. J. Clin. Pharmacol., 2000, 50(4), 325-332.
[http://dx.doi.org/10.1046/j.1365-2125.2000.00264.x] [PMID: 11012555]
[29]
Lewis, S.J.; Heaton, K.W. The metabolic consequences of slow colonic transit. Am. J. Gastroenterol., 1999, 94(8), 2010-2016.
[http://dx.doi.org/10.1111/j.1572-0241.1999.01271.x] [PMID: 10445521]
[30]
Nauli, A.M.; Nauli, S.M. Intestinal transport as a potential determinant of drug bioavailability. Curr. Clin. Pharmacol., 2013, 8(3), 247-255.
[http://dx.doi.org/10.2174/1574884711308030012] [PMID: 23343017]
[31]
Musial, B.L.; Chojnacki, J.K.; Coleman, C.I. Atazanavir: A new protease inhibitor to treat HIV infection. Am. J. Health Syst. Pharm., 2004, 61(13), 1365-1374.
[http://dx.doi.org/10.1093/ajhp/61.13.1365] [PMID: 15287232]
[32]
Hautekeete, M.L. Hepatotoxicity of antibiotics. Acta Gastroenterol. Belg., 1995, 58(3-4), 290-296.
[PMID: 7491842]
[33]
Lee, B.L.; Delahunty, T.; Safrin, S. The hydroxylamine of sulfamethoxazole and adverse reactions in patients with acquired immunodeficiency syndrome. Clin. Pharmacol. Ther., 1994, 56(2), 184-189.
[http://dx.doi.org/10.1038/clpt.1994.122] [PMID: 8062495]
[34]
Kobuchi, S.; Fukushima, K.; Aoyama, H.; Ito, Y.; Sugioka, N.; Takada, K. Effects of oxidative stress on the pharmacokinetics and hepatic metabolism of atazanavir in rats. Free Radic. Res., 2013, 47(4), 291-300.
[http://dx.doi.org/10.3109/10715762.2013.770149] [PMID: 23351068]
[35]
Hsu, A.; Granneman, G.R.; Bertz, R.J. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin. Pharmacokinet., 1998, 35(4), 275-291.
[http://dx.doi.org/10.2165/00003088-199835040-00002] [PMID: 9812178]
[36]
Chatton, J.Y.; Munafo, A.; Chave, J.P.; Steinhäuslin, F.; Roch-Ramel, F.; Glauser, M.P.; Biollaz, J. Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal excretion of zidovudine and its glucuronide. Br. J. Clin. Pharmacol., 1992, 34(6), 551-554.
[PMID: 1493087]
[37]
Suthar, A.B.; Vitoria, M.A.; Nagata, J.M.; Anglaret, X.; Mbori-Ngacha, D.; Sued, O.; Kaplan, J.E.; Doherty, M.C. Co-trimoxazole prophylaxis in adults, including pregnant women, with HIV: A systematic review and meta-analysis. Lancet HIV, 2015, 2(4), e137-e150.
[http://dx.doi.org/10.1016/S2352-3018(15)00005-3] [PMID: 26424674]
[38]
Kobuchi, S.; Fukushima, K.; Aoyama, H.; Ito, Y.; Sugioka, N.; Takada, K. Effects of obesity induced by high-fat diet on the pharmacokinetics of atazanavir in rats. Drug Metab. Lett., 2013, 7(1), 39-46.
[http://dx.doi.org/10.2174/18723128112066660016] [PMID: 24151827]
[39]
Amadasi, S.; Odolini, S.; Foca, E.; Panzali, A.; Cerini, C.; Lonati, L.; Pezzoli, M.C.; Nasta, P.; Casari, S.; Castelli, F.; Quiros-Roldan, E. Evaluation of boosted and unboosted atazanavir plasma concentration in HIV infected patients. Curr. HIV Res., 2013, 11(8), 642-646.
[http://dx.doi.org/10.2174/1570162X12666140207162225] [PMID: 24517189]
[40]
Joe, M.B.; Rolandc, L.; Laurentg, C.; Patrick, L.M.; Sawoo, O.; Gastonf, T.L.; Brunoe, E.; Gilles, P.; Philippe, P. Concomitant use of cotrimoxazole and atazanavir in HIV-infected patients: A therapeutic drug monitoring and pharmacovigilance based dual approach. Curr. Clin. Pharmacol., 2019. Epub ahead of print
[http://dx.doi.org/10.2174/1574884714666190405160612] [PMID: 30961507]