Universitas Indonesia Conferences, Asian Federation for Pharmaceutical Sciences (AFPS) 2019

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Effect of maternofetal albumin concentration gradient in rodents on interspecies difference in fetal drug transfer between rodents and human
Takehiro Nomura

Last modified: 2019-06-16


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 (Kp,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 (Kp,uu,fetus) in rats and to compare with Kp,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 (fu,fetus and fu,mother) was measured using equilibrium dialysis or ultrafiltration. Results: Rat Kp,fetus of digoxin and indomethacin were less than 38% of those in human. However, fu,fetus of these drugs were more than twice of fu,mother in rats, and consequently rat Kp,uu,fetus were calculated to be 0.85 and 1.00, which were higher than rat Kp,fetus but consistent with those in human. Rat Kp,fetus of phenobarbital was observed to be similar to human Kp,fetus, and the fu,fetus and fu,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 Kp,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 Kp,uu,fetus for extrapolating fetal drug transfer from rodents to human pregnancy.