[Molecular Biological Analysis of Factors Influencing Pharmacokinetics to Achieve Personalized Pharmacotherapy]

Yakugaku Zasshi. 2015;135(9):1037-41. doi: 10.1248/yakushi.15-00169.
[Article in Japanese]

Abstract

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.

Publication types

  • English Abstract
  • Review

MeSH terms

  • Animals
  • Cimetidine / metabolism
  • Cyclosporine / pharmacokinetics
  • Drug Therapy / methods
  • Glycoproteins / analysis
  • Humans
  • Liver / metabolism
  • Liver Transplantation
  • MicroRNAs / physiology
  • Precision Medicine / methods*
  • RNA Processing, Post-Transcriptional
  • Rats
  • Reperfusion Injury / metabolism

Substances

  • Glycoproteins
  • MicroRNAs
  • Cimetidine
  • Cyclosporine