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Metabolic interaction between cyclosporine and sirolimus
Shuang Bai1, Stanislaw M Stepkowski, Barry D Kahan
1Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712-0126, USA.
Transplantation
|July 9, 2004
Summary
Co-administering cyclosporine (CsA) and sirolimus (SRL) in rats significantly impacts drug metabolism and transport. Combined CsA and SRL therapy causes greater inhibition of cytochrome P450 3A1/2 and increased P-glycoprotein levels, potentially leading to unpredictable drug effects.
Area of Science:
- Pharmacology
- Drug Metabolism
- Transplant Medicine
Background:
- Cyclosporine (CsA) and sirolimus (SRL) are immunosuppressants used in transplant patients.
- Co-administration of CsA and SRL can lead to drug interactions due to shared metabolic and transport pathways.
- Both drugs influence cytochrome P450 3A1/2 (CYP3A1/2) and P-glycoprotein (Pgp) activity.
Purpose of the Study:
- To investigate the role of metabolic enzymes and membrane transporters in CsA and SRL disposition.
- To examine the effects of chronic CsA and SRL therapy on hepatic CYP3A1/2, Pgp, and multidrug resistance gene (mdr) mRNA levels in rats.
Main Methods:
- Rats received intravenous doses of CsA (2.5 mg/kg) and SRL (1 mg/kg) alone or in combination for two weeks.
- Hepatic CYP3A1/2 and Pgp protein expression, catalytic activity, and mdr mRNA levels were analyzed.
Main Results:
- CsA inhibited CYP3A1/2 expression, activity, and mRNA. SRL suppressed CYP3A1/2 protein and activity but not mRNA.
- Combined CsA and SRL therapy resulted in greater CYP3A1/2 inhibition.
- Both drugs increased Pgp protein levels and mdr1a/mdr1b mRNA expression, with the greatest increase seen with combined dosing.
Conclusions:
- CYP3A1/2 and Pgp are key players in the disposition of CsA and SRL in rats.
- Altered CYP3A1/2 and Pgp activity during combined therapy may cause unpredictable drug interactions and effects.