title: Metronidazole or Cotrimoxazole therapy is associated with a decrease in intestinal bioavailability of common antiretroviral drugs.
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.
authors.affiliation: Laboratoire de Biologie, CNAM, Paris, France.
authors.forename: Flore
authors.initials: F
authors.lastname: Dossou-Yovo
authors.affiliation: University of Paris Diderot - Paris 7, Faculty of Medicine Xavier Bichat, Laboratory TBC TransCell-Lab, Paris, France.
authors.forename: Godefroy
authors.initials: G
authors.lastname: Mamadou
authors.affiliation: University of Paris Diderot - Paris 7, Faculty of Medicine Xavier Bichat, Laboratory TBC TransCell-Lab, Paris, France ; Institut Universitaire des Sciences et Technique d'Abéché, N'Djamena, Tchad.
authors.forename: Imar Djibrine
authors.initials: ID
authors.lastname: Soudy
authors.affiliation: University of Paris Diderot - Paris 7, Faculty of Medicine Xavier Bichat, Laboratory TBC TransCell-Lab, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Limas-Nzouzi
authors.affiliation: University of Paris Diderot - Paris 7, Faculty of Medicine Xavier Bichat, Laboratory TBC TransCell-Lab, Paris, France.
authors.forename: Joe
authors.initials: J
authors.lastname: Miantezila
authors.affiliation: Académie Nationale de Médecine, Paris, France.
authors.forename: Jehan-François
authors.initials: JF
authors.lastname: Desjeux
authors.affiliation: University of Paris Diderot - Paris 7, Faculty of Medicine Xavier Bichat, Laboratory TBC TransCell-Lab, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Eto
mesh_terms: D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate; D001682:Biological Availability; D003106:Colon / Q000187:drug effects / Q000502:physiology; D004553:Electric Conductivity; D015658:HIV Infections / Q000188:drug therapy*; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage / Q000494:pharmacology*; D009842:Oligopeptides / Q000493:pharmacokinetics; D011725:Pyridines / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000493:pharmacokinetics; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D044966:Anti-Retroviral Agents; D009842:Oligopeptides; D011725:Pyridines; D008795:Metronidazole; D000069446:Atazanavir Sulfate; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D019438:Ritonavir