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

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Irbesartan has lower fetal toxicity and transfer compared to olmesartan in rats
Yu Ishikawa

Last modified: 2019-06-16


Background: Angiotensin II receptor blockers (ARBs) are contraindicated in pregnancy due to their fetal toxicity, oligohydramnios. We analysed the reported frequencies of adverse events using FDA-adverse event reporting system and revealed that reported incidence ratios of ARBs against representative adverse events such as renal failure are similar between ARBs but that against oligohydramnios of irbesartan (IRB) is much lower than olmesartan (OLM). These results led us to hypothesize that IRB has lower adverse fetal effect compared to OLM. Objective: This study aimed to clarify the differences in fetal toxicity between IRB and OLM in hypertensive disorder of pregnancy (HDP) model rats. Methods: IRB and OLM were administrated orally once a day or by constant subcutaneous pump infusion to L-NAME-induced HDP model rats or pregnant rats, from gestational day (GD) 17.5 to 20.5. The fetal toxicity and transfer of ARBs was evaluated by fetal weight and fetal to maternal concentration ratio at GD 20.5, respectively. The plasma unbound concentration was measured by equilibrium dialysis. The transport function of transporters was measured by uptake study using HEK293 cells. Results: HDP model rats showed hypertension and the blood pressure was reduced to normal level by administration of both IRB and OLM.  Contrary to the hypotensive effect, the fetal weight was significantly decreased only in OLM-treated rats. To investigate fetal transfer of the ARBs, we measured the fetal and maternal plasma concentration. The maternal to fetal plasma unbound concentration ratio of IRB and OLM were 0.33 and 1.9, respectively. Organic anion transporting polypeptides OATP2B1 is expressed at the fetal facing membrane of syncytiotrophoblast, the blood-placenta barrier. We found that human OATP2B1 showed significant uptake of IRB but little uptake of OLM. Conclusion: IRB showed lower fetal toxicity and transfer compared to OLM. It is possible that OATP2B1 is involved in fetal-to-maternal transport of IRB.