Abstract
Background. Cyclosporine is a potent immunosuppressant known 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 216-223 |
| Number of pages | 8 |
| Journal | Kidney International |
| Volume | 54 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1998 |
| Externally published | Yes |
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Keywords
- Cyclosporine nephropathy
- Cytochrome
- Hepatic isoforms
- Immunosuppression
- Metabolism
- Nephrotoxicity
- Pharmacokinetics
ASJC Scopus subject areas
- Nephrology
Cite this
Cyclosporine suppresses rat hepatic cytochrome P450 in a time-dependent manner. / Brunner, Lane J.; Bennett, William M.; Koop, Dennis.
In: Kidney International, Vol. 54, No. 1, 1998, p. 216-223.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cyclosporine suppresses rat hepatic cytochrome P450 in a time-dependent manner
AU - Brunner, Lane J.
AU - Bennett, William M.
AU - Koop, Dennis
PY - 1998
Y1 - 1998
N2 - Background. Cyclosporine is a potent immunosuppressant known 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.
AB - Background. Cyclosporine is a potent immunosuppressant known 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.
KW - Cyclosporine nephropathy
KW - Cytochrome
KW - Hepatic isoforms
KW - Immunosuppression
KW - Metabolism
KW - Nephrotoxicity
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=0031860936&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031860936&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.1998.00970.x
DO - 10.1046/j.1523-1755.1998.00970.x
M3 - Article
VL - 54
SP - 216
EP - 223
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 1
ER -