[Molecular Biological Analysis of Factors Influencing Pharmacokinetics to Achieve Personalized Pharmacotherapy].
Large individual variations in drug efficacy and safety could be explained in part by pharmacokinetics regulated by drug transporters and drug-metabolizing enzymes. However, expression and/or function of these proteins often fluctuate in pathological conditions, causing individual pharmacokinetic variability. To achieve a personalized pharmacotherapy after liver transplantation, our group has been investigating the pharmacokinetics of drugs and factors causing its variation based on molecular biological analysis using rats with liver ischemia-reperfusion (I/R) injury as a model for injuries immediately after liver transplantation. The first finding is that the oral bioavailability of cyclosporine A (CsA), which is an immunosuppressant, was decreased by increased first-pass metabolism due to elevated CYP3A and P-glycoprotein (P-gp) specifically in the upper small intestine after liver I/R. Expression of CYP3A in the small intestine was also elevated through transcriptional regulation by endogenous bile acids, whereas expression and function of intestinal P-gp were increased by post-transcriptional regulation via microRNA-145. Next, the pharmacokinetics of a cationic drug, cimetidine, which is eliminated from the kidney, and the expressional variation of drug transporters in the kidney after liver I/R were examined. Liver I/R decreased tubular secretion of cimetidine, mainly because of decreased expression of rat organic cation transporter 2 in the kidney. These findings provide useful information on the etiology of liver I/R injury and appropriate use of immunosuppressants and drugs eliminated from the kidney after liver transplantation.
Department of Pharmacy, Mie University Hospital.
Kenji
K
Ikemura
D000818:Animals; D002927:Cimetidine / Q000378:metabolism; D016572:Cyclosporine / Q000493:pharmacokinetics; D004358:Drug Therapy / Q000379:methods; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D008099:Liver / Q000378:metabolism; D016031:Liver Transplantation; D035683:MicroRNAs / Q000502:physiology; D057285:Precision Medicine / Q000379:methods*; D012323:RNA Processing, Post-Transcriptional; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism
D006023:Glycoproteins; D035683:MicroRNAs; D002927:Cimetidine; D016572:Cyclosporine