Metabolism for cyclosporin A during liver regeneration after partial hepatectomy in rats.
OBJECTIVE
To elucidate the metabolism and the effect of the cyclosporin A (CyA) as a representative immunosuppressive drug used in transplantation in a partially hepatectomized rat model.


METHODS
CyA was administered to rats that underwent a 70% hepatectomy. These rats were randomly assigned into three groups according to the dose of CyA administration as follows; (group 1) water, (group 2) 5 mg/kg CyA, (group 3) 10 mg/kg CyA. On postoperative days-1, 3, 7 and 14, the rats were killed to analyze the serum concentration of CyA, the liver regeneration ratio, biochemical or histological markers, and mRNA expression using reverse transcriptase-polymerase chain reaction method to determine albumin and cytochrome p450 expression.


RESULTS
The serum concentration of CyA in group 3 was significantly higher than group 2 during liver regeneration. CyA enhanced the liver regeneration in a dose dependent manner. The mRNA expression associated with CyA metabolism was significantly decreased on day 14, while preserving the albumin producing activity.


CONCLUSIONS
These data indicate that the p-450 activity required to metabolize the CyA may be reduced during regeneration of the remnant liver after a hepatectomy, which may, therefore, be linked to difficulty in controlling the optimal dose of CyA during early period of LDLT.
Nagayoshi
Shigeki
S
Department of Transplantation and Digestive Surgery, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
Kawashita
Yujo
Y
Eguchi
Susumu
S
Kamohara
Yukio
Y
Takatsuki
Mitsuhisa
M
Miyamoto
Shungo
S
Mochizuki
Satoshi
S
Soyama
Akihiko
A
Tokai
Hirotaka
H
Hidaka
Masaaki
M
Tajima
Yoshitsugu
Y
Kanematsu
Takashi
T
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D004305:Dose-Response Relationship, Drug; D006498:Hepatectomy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000601:surgery*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D012333:RNA, Messenger; D012709:Serum Albumin; D016572:Cyclosporine; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A