Effect of low dose cyclosporine and sirolimus on hepatic drug metabolism in the rat1.
BACKGROUND
We examined the effect cyclosporine (CsA) and sirolimus (SRL) alone and in combination on hepatic cytochrome P450-mediated metabolism in rats.


METHODS
Rats were given 1 mg/kg of CsA or 0.4 mg/kg of SRL alone or in combination via constant intravenous infusion. Renal function was evaluated at the end of treatment. Blood samples were obtained to estimate CsA and SRL concentrations. Hepatic microsomes were prepared for immunoblotting and catalytic assays.


RESULTS
CsA alone did not alter serum creatinine levels. SRL given alone or in combination with CsA produced a significant increase in urine output without changes in fluid balance. Although CsA and SRL administered alone caused damage to renal proximal tubules, the two-drug combination dramatically increased the renal structural damage. CsA alone suppressed cytochrome P450 (CYP) 3A2 protein levels by 39% (P=0.012) and catalytic activity by 30% (P=0.042). SRL alone reduced catalytic activity by 38% (P=0.012). Combination therapy reduced both CYP3A2 levels by 55% (P<0.001) and catalytic activity by 55% (P=0.001). CYP2C11 protein expression or catalytic activity were not changed in any group. CYP2A1 protein expression and catalytic activity were both significantly reduced in rats given CsA or/and SRL. Steady-state CsA levels were increased during concurrent SRL dosing, however, SRL concentrations were not changed by CsA coadministration.


CONCLUSIONS
Concurrent SRL dosing increases CsA concentrations due to inhibition of hepatic CYP3A2 protein expression. Nephrotoxicity caused by combination therapy is due to CsA elevating levels of SRL or by SRL itself. Concurrent administration of CsA and SRL in transplant patients should be performed with caution.
Bai
S
S
4 Address correspondence to: Lane J. Brunner, Ph.D., Pharmaceutics Division, PHR 4.214E, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712-1074.
Brunner
L J
LJ
Stepkowski
S M
SM
Napoli
K L
KL
Kahan
B D
BD
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology / Q000506:poisoning; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology / Q000506:poisoning; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D009994:Osmolar Concentration; D051381:Rats; D011916:Rats, Inbred F344; D020123:Sirolimus / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology / Q000506:poisoning; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; D020123:Sirolimus