title: Circadian variation of isoniazid pharmacokinetics in mice.
abstract: BACKGROUND
  This study is designed to investigate whether the pharmacokinetics of the antituberculous agent isoniazid (INH) varied according to the circadian dosing-time.
  
  
  METHODS
  A total of 168 male mice aged 10 weeks and synchronized for 3 weeks to 12h light and 12h dark were used. A single INH (100mg/kg) dose was administered by intraperitonal (i.p.) route at either of the four different circadian stages (1, 7, 13 and 19h after light onset, HALO). At each circadian stage, blood samples were withdrawn at 0, 0.1, 0.2, 0.4, 1, 1.3, 2, 2.5, 4, 5, 6.3, 8, 24 and 48h following drug injection. The pharmacokinetics parameters (AUC0-∞, Ke, Cmax, T 1/2, ClTand Vd) were calculated for each circadian-time.
  
  
  RESULTS
  There were relevant differences in Cmaxbetween the four circadian groups (p<0.005), maximum and minimum Cmaxwere obtained when INH was injected at 1 HALO (490mgL-1) and at 7 HALO (270mgL-1) respectively. AUC0-∞also varied significantly according to the circadian-time of injection (2093mgL-1h-1at 1 HALO vs 759mgL-1h-1at 7 HALO) (p<0.05). The highest and lowest mean values of plasma clearance (Cl) were observed at 7 HALO (0.22Lh-1kg-1) and 1 HALO (0.13Lh-1kg-1) respectively (p<0.05). The Cosinor analysis showed a circadian rhythm in different pharmacokinetic parameters. Cmaxand AUC0-∞have a significant circadian rhythm with an acrophase located at 2.64 HALO±0.21h (the beginning of the rest span) (p<0.001), whereas ClTand Vdshowed a significant circadian rhythm with an acrophase located respectively at 7.4 HALO and at 8.66 HALO (the second half of the rest span) (p<0.001).
  
  
  CONCLUSIONS
  Plasma INH chronopharmacokinetics might be involved in the mechanism of circadian variation of toxicity since the time of optimal tolerance to INH corresponds to that of the lowest Cmaxand AUC0-∞and the highest ClToccured when this drug injected in the second half of light-rest phase (7 HALO).
authors: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5019 Monatir, Tunisie. Electronic address: souayednouha@yahoo.fr.
authors: Nouha
authors: N
authors: Souayed
authors: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5019 Monatir, Tunisie. Electronic address: malek_chennoufi@yahoo.fr.
authors: Malek
authors: M
authors: Chennoufi
authors: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5019 Monatir, Tunisie. Electronic address: benfredj.nadia@gmail.com.
authors: Nadia Ben
authors: NB
authors: Frej
authors: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5019 Monatir, Tunisie. Electronic address: dr.amelchaabane@gmail.com.
authors: Amel
authors: A
authors: Chaabane
authors: Laboratory of Biomonitoring of the Environment (LR01/ES14), Faculty of Science Bizerta, University of Carthage, 7021 Bizerta, Tunisie. Electronic address: mobenattia@yahoo.fr.
authors: Mossadok
authors: M
authors: Ben-Attia
authors: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5019 Monatir, Tunisie. Electronic address: aouam_k@yahoo.fr.
authors: Karim
authors: K
authors: Aouam
authors: Unit of Chronobiology, Foundation A.-de-Rothschild, 75940 Paris, France. Electronic address: bergarien@yahoo.fr.
authors: Alain
authors: A
authors: Reinberg
authors: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5019 Monatir, Tunisie. Electronic address: naboughattas@yahoo.fr.
authors: Naceur A
authors: NA
authors: Boughattas
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D055870:Drug Chronotherapy; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007538:Isoniazid / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D017440:Photoperiod
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid
keywords: Blood samples; Circadian rhythm; Cosinor; Intraperitoneal route; Isoniazid; Mice; Pharmacokinetic