Comparison of pharmacokinetics of cyclosporine A in cadaveric and living-related renal transplant recipients and in an experimental rat model of renal failure.
To elucidate the differences in the cyclosporine A (CyA) PK between cadaveric and living-related renal transplantation (CRT and LRT, respectively) recipients, a retrospective cohort study of clinical PK was conducted. Data from 80 patients who received LRT (n=75) and CRT (n=5) over 4 years were included. The incidence of acute rejection in CRT recipients was over 5 times higher than that in LRT recipients. On day 14 after transplantation, the area under the blood concentration versus time curve (AUC) per dose up to 4 h in CRT recipients was 65.3 % that of LRT recipients, however, there was no difference in the blood trough levels. Unlike LRT, renal failure derived from long ischemia time was observed in CRT recipients, and it is speculated that renal failure affects the PK of CyA. Moreover, we performed intravenous. (i.v.) and intraduodenal (i.d.) PK studies of CyA using renal failure model rats prepared by renal ischemia-reperfusion (RIR rats). There were no differences in PK profiles after i.v. administration of CyA between RIR and control rats; however, AUC up to infinity (1.81+/-0.18 microg.h/ml) in RIR rats after i.d. administration was significantly lower than in control rats (5.01+/-1.78 microg.h/ml). In addition, the absorption of CyA and midazolam, an ideal probe for CYP3A, from the intestinal loop in RIR rats was significantly less (69.8% and 42.8 %, respectively) than in control rats. These results suggest that the contribution of intestinal metabolism by CYP3A to decreasing CyA absorption in RIR rats is significant, namely, there is a possibility that the reason for poor absorption of CyA in CRT recipients is increasing intestinal CYP3A activity is maybe renal injury derived from long renal ischemia. The results of this study provide a useful information for therapeutic drug monitoring of CyA in CRT recipients.
Sugioka
Nobuyuki
N
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan. nsugioka@mb.kyoto-phu.ac.jp
Fujimoto
Katsukuni
K
Tanaka
Yuka
Y
Fukushima
Keizo
K
Ito
Yukako
Y
Kokuhu
Takatoshi
T
Okamoto
Masahiko
M
Yoshimura
Norio
N
Takada
Kanji
K
D000208:Acute Disease; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D019540:Area Under Curve; D002648:Child; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004195:Disease Models, Animal; D016903:Drug Monitoring; D004386:Duodenum / Q000201:enzymology; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D016030:Kidney Transplantation / Q000009:adverse effects*; D019520:Living Donors; D008297:Male; D008874:Midazolam / Q000378:metabolism; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D015427:Reperfusion Injury / Q000097:blood / Q000150:complications / Q000378:metabolism*; D012189:Retrospective Studies; D013379:Substrate Specificity; D055815:Young Adult
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam