Optimization of Drug Administration in Special Populations Focusing on Drug Distribution

Abstract

Patients with special backgrounds such as organ dysfunction, elderly individuals, children, and pregnant or nursing women in whom the pharmacokinetics of an agent are expected to differ from those observed in the general patient population, are referred to as "special populations." Administration of drug therapy to these patients warrants close attention to and knowledge of altered pharmacokinetics to design appropriate personalized dosing regimens. In this study, we investigated the effects of hypothermia and renal impairment on drug pharmacokinetics, focusing on tissue distribution. Analysis of the effects of hypothermia on local liver kinetics of drugs revealed decreased activity of drug-metabolizing enzymes and transporters. Furthermore, we investigated in vivo drug pharmacokinetics and observed that blood drug concentrations increased with a decrease in the body temperature. However, the tissue concentration of midazolam (MDZ) remained unchanged even with a decrease in body temperature, which indicates reduced tissue transfer of MDZ. With regard to the effect of renal impairment, blood concentration of MDZ decreased in patients with acute renal failure and increased in those with chronic renal failure. However, MDZ clearance was decreased in patients with chronic renal failure owing to decreased expression of hepatic metabolic enzymes and reduced hepatic blood flow. This study highlights that tissue translocation of drugs differs across special populations and that optimization of drug administration based on the prediction of tissue concentrations is important.