Cyclosporine suppresses rat hepatic cytochrome P450 in a time-dependent manner.
BACKGROUND
Cyclosporine is a potent immunosuppressant know to selectively suppress specific cytochrome P450 (P450) isoforms following chronic therapy in the rat. Cyclosporine undergoes significant hepatic metabolism in the rat, primarily due to P450 3A isoforms. Hence, alterations in hepatic metabolism of cyclosporine may lead to changes in drug pharmacokinetics or pharmacodynamics. The purpose of this study was to examine the temporal effect of chronic cyclosporine dosing on P450 protein expression and metabolic activity in a rat model of chronic cyclosporine nephropathy.


METHODS
Adult male rats were administered cyclosporine 15 mg/kg/day or vehicle 1 ml/kg/day by subcutaneous injection for up to 28 days. To examine whether or not metabolic activity recovered following drug removal, additional rats were administered cyclosporine for 28 days followed by vehicle for up to an additional 15 days. Hepatic P450 protein expression and microsomal metabolic activity were measured by Western blot analysis and in vitro steroid hydroxylation, respectively.


RESULTS
Cyclosporine trough levels progressively increased over the 28 days period and were still measurable for up to 15 days after discontinuation. Immunoblot analysis indicated that chronic cyclosporine treatment suppressed P450 3A2 expression and in vitro steroid hydroxylation in a time-dependent manner. Fifteen days following discontinuation of cyclosporine dosing, hepatic metabolic activity and microsomal P450 3A2 levels returned to near pre-dosing levels.


CONCLUSIONS
We conclude that the time-dependent P450 suppression by cyclosporine may at least partially explain the variability in cyclosporine pharmacokinetics. These studies support the hypothesis that hepatic isoforms other than P450 3A2 may be responsible for cyclosporine metabolism during chronic treatment in the rat.
Brunner
L J
LJ
Pharmaceutics Division, College of Pharmacy, University of Texas at Austin, USA. ljb@mail.utexas.edu
Bennett
W M
WM
Koop
D R
DR
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D003404:Creatinine / Q000652:urine; D016572:Cyclosporine / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D006900:Hydroxylation; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D007677:Kidney Function Tests; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009994:Osmolar Concentration; D011188:Potassium / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors
D015415:Biomarkers; D007166:Immunosuppressive Agents; D013739:Testosterone; D000735:Androstenedione; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D011188:Potassium