title: The dosing-time dependent influence of chronic cyclosporin A treatment on daily profiles of plasma glucose and insulin in the Wistar rat.
abstract: The dosing-time dependent effects of cyclosporin A (CsA) on glucose and insulin plasma levels were evaluated in the light of possible alterations of their biological rhythms. Male Wistar rats weighing 200-250 g were habituated to a 12:12 h light-dark cycle. At the beginning of the experiments, on day D0 (before any treatment), significant rhythms were obtained for plasma glucose and immunoreactive insulin (IRI). The plasma glucose showed a 12 h periodicity and the plasma IRI a more pronounced rhythm, with both 12 h and 24 h significant components. Plasma glucose and IRI were then determined in drug-treated (20 mg CsA/kg b.wt/day; dosing time point: T01, T07, T13, or T20) and control rats during and after a 21-day treatment period. The CsA-treated rats developed hyperglycemia and a marked enhancement of the amplitude of the daily glucose rhythm. The magnitude of these effects differed among the groups (p < 0.001). Most pronounced alterations were observed on day 21 (D21) in group T07: M = 22.5 +/- 4.0 mmol/l; A = 9.2 +/- 6.0 mmol/l. The mean plasma insulin showed little though significant (p < 0.01) decreases. For instance, on D21 in group T01, M = 28.5 +/- 3.6 microU/ml, and in group T07, M = 28.7 +/- 2.5 microU/ml. In parallel, plasma CsA levels increased during the 21-day period and differed among groups (p < 0.01). The highest levels (4-5 mg/l) were obtained in T07 and T19 on D21. After drug cessation, the levels of plasma glucose were reduced, but stayed higher than control values. Body weights were monitored; the rate of growth was lower (p < 0.01) in CsA-treated rats than in controls (2.93 +/- 0.11 versus 5.1 +/- 0.11 g/day, respectively).
authors.affiliation: Equipe Cinétique des Xénobiotiques, Faculté des Sciences Pharmaceutiques, Université Paul Sabatier, Toulouse, France.
authors.forename: M F
authors.initials: MF
authors.lastname: Malmary
authors.forename: S
authors.initials: S
authors.lastname: Moussamih-Kettani
authors.forename: C
authors.initials: C
authors.lastname: Labat
authors.forename: J
authors.initials: J
authors.lastname: Oustrin
authors.forename: G
authors.initials: G
authors.lastname: Houin
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002940:Circadian Rhythm / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity*; D004334:Drug Administration Schedule; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity*; D007328:Insulin / Q000097:blood*; D008297:Male; D010507:Periodicity; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D007166:Immunosuppressive Agents; D007328:Insulin; D016572:Cyclosporine