Blood endocrine disruptor levels in cryptorchidic newborns

Abstract

Non-clinical safety evaluation using juvenile animals is becoming more important in development of medicinal products for paediatric use. It is considered that many physiological changes occur in juvenile animals during their development and this could affect toxicokinetics (TK) and toxicodynamics (TD) of some drugs. However, the changes in TK caused by physiological development have not been fully investigated. Our previous study showed many differences between juvenile and adult rats, in concentration of serum proteins, mRNA expression of CYP enzymes and transporters, and so on. In this study, TK analysis of single dose study in juvenile rats treated with quinidine, which binds mainly to a1-acid glycoprotein (AGP), was conducted to assess the impact on TK. Quinidine at a dose of 30mg/kg was administered intravenously to 14-, 21and 49-day-old rats (n=4/sex/age), and its concentration in plasma was analyzed. As a result, the AUCall of quinidine decreased with sex maturation between 21and 49-day-old rats from 10,500 to 6900ngh/mL (males), and from 8200 to 5710ngh/mL (females). This decrease is considered to be caused mainly by faster elimination of quinidine in 49-day-old rats because z, the elimination rate constant, increased with age between 21and 49-day-old rats from 0.290 to 0.660 (1/h) in males, 0.306 to 0.842 (1/h) in females. In this presentation, the mechanism of these differences and its impact on TK will be discussed.