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. 2014 Feb 26;9(2):e89943.
doi: 10.1371/journal.pone.0089943. eCollection 2014.

Metronidazole or Cotrimoxazole therapy is associated with a decrease in intestinal bioavailability of common antiretroviral drugs

Flore Dossou-Yovo  1 , Godefroy Mamadou  2 , Imar Djibrine Soudy  3 , Nicolas Limas-Nzouzi  2 , Joe Miantezila  2 , Jehan-François Desjeux  4 , Bruno Eto  2
Affiliations

Metronidazole or Cotrimoxazole therapy is associated with a decrease in intestinal bioavailability of common antiretroviral drugs

Flore Dossou-Yovo et al. PLoS One. .

Abstract

Metronidazole (MTZ) and Cotrimoxazole (CTX) are used in HIV/AIDS patients eligible for antiretroviral treatment. The objective of this animal study was to determine whether pre-treatment with antibiotics affects the intestinal bioavailability of Atazanavir (ATV) and Ritonavir (RTV). After oral administration of 1 mg MTZ and CTX for 7 days, the rat colonic mucosa were analyzed for mucus thickness or placed in Ussing chambers to measure ATV and RTV net transepithelial fluxes (Jnet). 1. In control rats, the mucus thickness was 43.3±7.6 µm and 40.7±6.9 µm, in proximal and distal colon, respectively. In proximal colon, the thickness was 57.2±8.8 and 58.2±6.9 µm after MTZ and CTX, respectively whereas in distal colon, the thickness was 121.1±38.4 and 170.5±35.0 µm (P<0.05) respectively. 2. Transepithelial conductance was reduced after MTZ or CTX in the proximal and distal colon. 3. In control, net ATV secretion was observed both in proximal (-0.36±0.02 µg.hr(-1) cm(-2)) and distal colon (-0.30±0.08 µg.hr(-1) cm(-2)). After MTZ and CTX, it was increased in the proximal colon by two 2 fold and 4 fold, respectively and in the distal colon by 3 fold and 5 fold, respectively. 4. In control, there was no net active RTV transport either in proximal (+0.01±0.01 µg.hr(-1) cm(-2)) or distal colon (+0.04±0.01 µg.hr(-1) cm(-2)). After MTZ and CTX, secretion was increased 5 fold and 10 fold, respectively, in the proximal colon and two fold and 5 fold, respectively in the distal colon (p<0.001). In conclusion, after MTZ and CTX therapy, the mucus layer was enlarged, passive permeability was decreased and ATV and RTV were actively secreted by the colonic epithelium suggesting that, in rat, the intestinal bioavailability of ATV and RTV is impaired after antibiotic therapy.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Thickness of the total mucus layer in colonic mucosa in proximal 2) and distal segments 3) of control a), Metronidazole b) and Cotrimoxazole-treated rats c), AB/PAS staining.
1) Magnification x 100 and x 400. The total mucus thickness (M) was measured as a continuous layer between the luminal surface (L) and epithelium (E). Increased thickness of the mucus layer was observed in MTZ and CTX treated rats (b, c). Goblet cells are filled with mucus (blue arrows) either in the control or the MTZ and CTX treated group. Occasionally, a separation could be observed between the mucus layer and the epithelial surface, and may be due to the partial mucus shrinkage during the histological procedure .
Figure 2
Figure 2. Mucus thickness of colonic mucus (mean ± SE) after 1 week pre-treatment with 1 mg of Cotrimoxazole (CTX) or 1 mg of Metronidazole (MTZ), compared to control in proximal and distal colon.
*P<0.05 and ***P<0.001, n = 24 tissues from 7 rats.
Figure 3
Figure 3. Transepithelial electrical conductance (Gt) (mean ± SE) after 1 week of pre-treatment with 1 mg of Cotrimoxazole (CTX) or 1 mg of Metronidazole (MTZ) compared to controls, in proximal (A) and distal (B) colon.
*p<0.05, ***P<0.001, n = 24 tissues from 7 rats.
Figure 4
Figure 4. Relationship between Mucus thickness (in µm) and Transepithelial electrical Conductance Gt (in mS/cm2).
The data were obtained from the means of at least n = 13 tissues from 7 rats. Closed black dots indicate proximal colon and closed red dots distal colon (A). The relationship between Gt and mucus thickness (ML) were analyzed by nonlinear regression (curve fit) using the power series equation Y = AXb (B). r2 was 0.94. With 95% confidence limit if of A of 168.6 to 374.6 and B of −0.73 to −0.55, with covariance Matrix A and B = −0.99. Below the threshold of 42 µm the conductance (an index of ionic permeability) remained constant 25 mS/cm2. In contrast, the conductance decreased with mucus thickness down to a limit value of 10 mS/cm2.
Figure 5
Figure 5. ATV transepithelial net fluxes (Jnet) (mean ± SE) after 1 week of pre-treatment with 1 mg of Cotrimoxazole (CTX), or 1 mg of Metronidazole (MTZ) compared to controls, in proximal and distal colon.
***p<0.001, n = 12 tissues from 4 rats. Negative Jnet indicates secretion from serosal (blood) to mucosal (luminal) side.
Figure 6
Figure 6. RTV transepithelial net fluxes (Jnet) (mean ± SE) after 1 week of pre-treatment with 1 mg of Cotrimoxazole (CTX) or 1 mg of Metronidazole (MTZ) compared to controls, in proximal and distal tissues.
***p<0.001, n = 12 tissues of 4 rats.
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References

    1. Vogel M, Voigt E, Michaelis HC, Sudhop T, Wolff M, et al. (2004) Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients. Liver Transpl 10: 939–944. - PubMed
    1. Crommentuyn KM, Mulder JW, Sparidans RW, Huitema AD, Schellens JH, et al. (2004) Drug-drug interaction between itraconazole and the antiretroviral drug lopinavir/ritonavir in an HIV-1-infected patient with disseminated histoplasmosis. Clin Infect Dis 38: e73–75. - PubMed
    1. McIsaac WJ, Prakash P, Ross S (2008) The management of acute uncomplicated cystitis in adult women by family physicians in Canada. Can J Infect Dis Med Microbiol 19: 287–293. - PMC - PubMed
    1. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, et al... (2009) Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 58: 1–207; quiz CE201–204. - PubMed
    1. Pelissier MA, Vasquez N, Balamurugan R, Pereira E, Dossou-Yovo F, et al. (2010) Metronidazole effects on microbiota and mucus layer thickness in the rat gut. FEMS Microbiol Ecol 73: 601–610. - PubMed

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