Time-dependent pharmacokinetics and toxicity of cyclosporine.
Although the circadian pattern of cyclosporine (CSA) pharmacokinetics and toxicity has been described previously in both animal and clinical studies, the mechanism of this action is unknown. The present study compared the pharmacokinetics and experimental nephrotoxicity of chronic CSA in both the genetically-hyperlipidemic rat model and the lean litter-mate. Once daily dosing (25 mg/kg via gavage) was either at the start of the active (1900) or inactive (0700) cycle (Nov 1987 to Jan 1988). Serial serum samples following the final dose were assayed by both polyclonal (nonspecific) and monoclonal (specific for parent CSA) RIA. Renal toxicity was assessed by 24-hr creatinine clearances, fractional clearances of sodium and potassium, and inulin clearances (CIN). Despite a greater than 2-fold increase in serum CSA concentrations, there were no changes in renal function in obese rats dosed at the start of the active period compared to the inactive period. Furthermore, mean CIN of the lean group administered drug at the start of the active period was not significantly different from time-matched placebo-treated lean rats. However, there was an 80% drop in CIN in rats treated with CSA at the start of the inactive period compared to control group. There were no differences in electrolyte handling. Insulin concentrations, independent of time of dosing, were markedly elevated in obese rats dosed CSA compared to placebo-treated obese or both lean groups. Serum triglyceride levels were significantly correlated with pharmacokinetic parameters of total but not parent CSA. In summary, significant differences in toxicity were observed due to time of dosing and lipid profiles. Although the mechanism of this action remains unclear, it appears that increased non-fasting serum triglyceride levels following the active period most likely reduced CSA distribution into kidney tissue preventing the dose-limiting nephrotoxicity.
Luke
D R
DR
Department of Pharmaceutics, College of Pharmacy, University of Houston, Texas 77030.
Vadiei
K
K
Brunner
L J
LJ
D000818:Animals; D002940:Circadian Rhythm; D003404:Creatinine / Q000378:metabolism; D003524:Cyclosporins / Q000493:pharmacokinetics* / Q000633:toxicity; D007328:Insulin / Q000097:blood; D007444:Inulin; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011188:Potassium / Q000652:urine; D051381:Rats; D011924:Rats, Zucker; D012964:Sodium / Q000652:urine; D014280:Triglycerides / Q000097:blood
D003524:Cyclosporins; D007328:Insulin; D014280:Triglycerides; D007444:Inulin; D012964:Sodium; D003404:Creatinine; D011188:Potassium