Pharmacokinetics of cyclosporine A after massive hepatectomy: a hint for small-for-size graft in living donor liver transplantation.
In living donor liver transplantation, graft size is very important, and various studies have been conducted regarding these problems in small-for-size (SFS) grafts. The administration of immunosuppressants for SFS graft, in which the functional liver mass is small and necessary for excessive liver regeneration, has not been reported so far. The aims of this study were to investigate the optimal administration of cyclosporine (CyA) and characteristics of metabolism of CyA, according to liver volume. Seven-week-old male Wister rats were randomly divided into four groups: two CyA-administered groups (CyA groups), 70% and 90% hepatectomy (Hx); and two control groups, 70% and 90% Hx. The 70% Hx and 90% Hx were used as the surrogate model of SFS for 30% and 10% graft models. In CyA groups, CyA (5 mg/kg/day) was given for 3 days before Hx and after surgery until sacrifice. Animals were sacrificed at 0, 12, 24, 48, and 72 hr after Hx. The blood concentration of CyA and the expression of the CYP3A2 gene were measured at each point in CyA groups, and liver regeneration was evaluated by measuring the ratio of remnant liver weight to body weight in each group. Regarding the blood concentration of CyA, no difference was recognized between 30% and 10% graft models except for 72 hr after Hx. As for liver regeneration, no significant difference was recognized. Regarding the expression of CYP3A2, no change was noted in the 30% graft model; on the other hand, CYP3A2 expression was reduced. Significant differences between the 30% and the 10% graft model were observed 48 and 72 hr after Hx. The blood concentration of CyA was not dependent on the volume of the liver graft.
Shinohara
Hisamitsu
H
Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima, 770-8503, Japan.
Shimada
Mitsuo
M
Ogasawara
Takashi
T
Morine
Yuji
Y
Ikemoto
Tetsuya
T
Imura
Satoru
S
Fujii
Masahiko
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006498:Hepatectomy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D008099:Liver / Q000033:anatomy & histology* / Q000378:metabolism / Q000601:surgery; D008107:Liver Diseases / Q000097:blood* / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects*; D016031:Liver Transplantation / Q000502:physiology*; D019520:Living Donors; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009929:Organ Size; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar
D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D012333:RNA, Messenger; D016572:Cyclosporine; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A