Font Size: 

Background: At term, the serum albumin level in the fetus is similar to the maternal level, while the fetal/maternal ratio is about 0.5 in rat. This difference would cause lower fetal-to-maternal plasma concentration ratio (K_p,fetus) of some drugs in rat compared with human, due to lower fetal accumulation of albumin-bound drugs in rat. Therefore, the extrapolation of fetal drug transfer to human is expected to be improved with the use of unbound drug concentrations. Objective: This study aims to evaluate the fetal transfer by unbound fetal-to-maternal concentration ratio (K_p,uu,fetus) in rats and to compare with K_p,fetus in rat and human. Materials and Methods: Drugs were administrated continuously for 72 hr to pregnant rats from gestational day 16.5. Plasma drug concentration was quantified using LC-MS/MS, and the unbound fraction in plasma (f_u,fetus and f_u,mother) was measured using equilibrium dialysis or ultrafiltration. Results: Rat K_p,fetus of digoxin and indomethacin were less than 38% of those in human. However, f_u,fetus of these drugs were more than twice of f_u,mother in rats, and consequently rat K_p,uu,fetus were calculated to be 0.85 and 1.00, which were higher than rat K_p,fetus but consistent with those in human. Rat K_p,fetus of phenobarbital was observed to be similar to human K_p,fetus, and the f_u,fetus and f_u,mother in rat were also equivalent. These results indicate that lower plasma protein binding in the fetus causes superficial underestimation in fetal transfer of certain drugs in rat. It should be noted that, in the case of metformin and nitrazepam, the interspecies differences in K_p,fetus were observed but cannot be explained by the plasma protein binding. Conclusion: Since the maternofetal albumin concentration gradient in rat would affect interspecies difference in fetal transfer of certain drugs, it is more appropriate to use K_p,uu,fetus for extrapolating fetal drug transfer from rodents to human pregnancy.