Pharmacokinetics of Tacrolimus and Trimethadione after Canine Liver Transplantation

Masaaki Otsuka, Akio Ishikawa, Kenji Yuzawa, Hiroyuki Iida, Tadashi Kondo, Shinya Adachi, Takeshi Todoroki, Katashi Fukao, Einosuke Tanaka*

Institute of Clinical Medicine, *Institute of Community Medicine University of Tsukuba

To study the effect of ischemic injury on drug metabolism after liver transplantation, the pharmacokinetics of tacrolimus and trimethadione (TMO) were examined after canine liver transplantation. Tacrolimus (0.3 mg/kg) was administered intravenously over 30 minutes. Whole blood levels of tacrolimus were determined by ELISA. TMO (4 mg/kg) was rapidly injected intravenously. Serum levels of TMO and its metabolite dimethadione (DMO) were determined by gas chromatography. Pharmacokinetic analysis was made on the 1st and 7th posttransplant days, and compared with the control group in which the animals did not undergo the operation. Animals of both groups received an oral dose of tacrolimus (0.3 mgl/kg) on the other post-operative days. On the 1st post-transplant day, the clearance of TMO and serum ratio of DMO/TMO 2 hours after the administration were 0.94±0.41 ml/min/kg and 0.22±0.13 in the liver transplant group (n=5). These were significantly lower than those of the control group (2.43±0.78 ml/min/kg and 0.91±0.30, n=5). On the 7th post-transplant day, the clearance of TMO and the serum ratio of DMO/TMO were 3.65±7.74 ml/min/kg and 1.35±0.96 in the transplant group. No statistical difference was found between the two groups. The clearance and the whole blood levels 24 hours after the administration were compared to evaluate the pharmacokinetics of tacrolimus. No statistical differences were found between the transplant group and the control group on the 1st or 7th post-transplant day. The results indicate that the metabolism of TMO is more vulnerable to ischemic injury than that of tacrolimus. This suggests a difference in susceptibility to ischemia between P450 subspecies.

Key words
liver transplantation, pharmacokinetics, tacrolimus, trimethadione

Reprint requests
Masaaki Otsuka Institute of Clinical Medicine, University of Tsukuba
1-1-1 Tennoudai, Tsukuba-shi, 305 JAPAN

Accepted
October 11, 1995

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