RT Journal Article
SR Electronic
T1 The Effect of Lipoprotein-Associated Cyclosporine on Drug Metabolism and Toxicity in Rats
JF PDA Journal of Pharmaceutical Science and Technology
JO PDA J Pharm Sci Technol
FD Parenteral Drug Association (PDA)
SP 410
OP 424
VO 57
IS 6
A1 Taekrho Kim
A1 Shirley K. Lu
A1 Lane J. Brunner
YR 2003
UL http://journal.pda.org/content/57/6/410.abstract
AB Purpose: The objective of the study was to examine the effect of lipoprotein-associated cyclosporine on hepatic metabolism, hepatic lipoprotein receptors, and renal toxicity in comparison to the current commercially available cyclosporine (CSA) product. Methods: Rats within the same group were given one of the following treatments: 10 mg/kg of CSA, plasma-CSA, very low-density lipoprotein (VLDL)-CSA, low-density lipoprotein (LDL)-CSA, LDL, high-density lipoprotein (HDL)-CSA, 1 mL/kg of vehicle, or saline intravenously for 14 days. Urine and blood samples were evaluated for renal function. Hepatic microsomes were prepared for immunoblotting and in vitro catalytic assays of CYP activity. Reverse transcription polymerase chain reaction (RT-PCR) was used to examine genetic regulation. Results: (1) There were no statistical differences in cholesterol levels in lipoprotein-associated CSA groups as compared with vehicle controls. (2) A significant decrease in creatinine clearance was seen in the plasma-CSA treated group (56%; P < 0.05). (3) No suppressions of CYP3A protein, activity or mRNA were found in the VLDL-CSA treated group. (4) CYP3A mRNA was suppressed to a greater degree in the LDL- and HDL-CSA treated groups as compared with the suppression caused by CSA alone. (5) A significant suppression of hepatic low-density lipoprotein receptor (LDL-R) mRNA levels was found in the LDL-CSA (50%; P = 0.0333) and plasma-CSA (40%; P = 0.1138), which was not attributed to LDL alone. (6) Significant suppression of scavenger-receptors class B type I (SR-BI) mRNA levels was found in the plasma-CSA group, although no significant differences in SRBI protein levels were seen between groups. Conclusions: Specific lipoprotein-CSA complexes appear to alter metabolic responses differently in comparison to CSA alone, indicating that the metabolism of CSA is dependent on the in vivo disposition of lipoprotein-CSA. Furthermore, LDL-R is one regulatory factor responsible for altering CSA metabolism as a result of an increase in uptake of CSA into hepatocytes.