THE DOSING-TIME DEPENDENT INFLUENCE OF CHRONIC CYCLOSPORINE-A TREATMENT ON DAILY PROFILES OF PLASMA-GLUCOSE AND INSULIN IN THE WISTAR RAT

The dosing-time dependent effects of cyclosporin A (CsA) on glucose an d insulin plasma levels were evaluated in the light of possible altera tions of their biological rhythms. Male Wistar rats weighing 200-250 g were habituated to a 12:12h light-dark cycle. At the beginning of the experiments, on day DO (before any treatment), significant rhythms we re obtained for plasma glucose and immunoreactive insulin (IRI). The p lasma glucose showed a 12h periodicity and the plasma IRI a more prono unced rhythm, with both 12h and 24h significant components. Plasma glu cose and IRI were then determined in drug-treated (20 mg CsA/kg b.wt/d ay; dosing time point: T01, T07, T13, or T20) and control rats during and after a 21-day treatment period. The CsA-treated rats developed hy perglycemia and a marked enhancement of the amplitude of the daily glu cose 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 me an plasma insulin showed little though significant (p < 0.01) decrease s. For instance, on D21 in group T01, M = 28.5 +/- 3.6 mu U/ml, and in group T07, M = 28.7 +/- 2.5 mu U/ml. In parallel, plasma CsA levels i ncreased 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. A fter drug cessation, the levels of plasma glucose were reduced, but st ayed 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).