PT - JOURNAL ARTICLE AU - Jinfu Peng AU - Mayur K Ladumor AU - Jashvant D. Unadkat TI - <strong>Prediction of pregnancy-induced changes in secretory and total renal clearance of </strong><strong>drugs transported by organic anion transporters </strong> AID - 10.1124/dmd.121.000557 DP - 2021 Jan 01 TA - Drug Metabolism and Disposition PG - DMD-AR-2021-000557 4099 - http://dmd.aspetjournals.org/content/early/2021/07/27/dmd.121.000557.short 4100 - http://dmd.aspetjournals.org/content/early/2021/07/27/dmd.121.000557.full AB - Pregnancy can significantly change the pharmacokinetics of drugs, including those renally secreted by organic anion transporters (OATs). Quantifying these changes in pregnant women is logistically and ethically challenging. Hence, predicting the in vivo plasma renal secretory clearance and renal clearance of OAT drugs in pregnancy is important to design correct dosing regimens of OAT drugs. Here, we first quantified the fold-change in renal OAT activity in pregnant vs. non-pregnant individual using available selective OAT probe drug data (training dataset; OAT1: tenofovir, OAT2: acyclovir, OAT3: oseltamivir carboxylate). The fold-change in OAT1 activity during the 2nd and 3rd trimester was 2.9 and 1.0 compared to nonpregnant individual, respectively. OAT2 activity increased 3.1-fold during the 3rd trimester. OAT3 activity increased 2.2, 1.7 and 1.3-fold during the 1st, 2nd and 3rd trimester, respectively. Based on these data, we predicted the secretory clearance, renal clearance and total clearance of drugs in pregnancy, which are secreted by multiple OATs (verification dataset; amoxicillin, pravastatin, cefazolin and ketorolac, R-ketorolac, S-ketorolac). Then, the predicted CLs were compared with the observed values. The predicted/observed secretory clearance, renal clearance and total clearance of drugs in pregnancy of all verification drugs were within 0.80-1.25 fold except for of amoxicillin in the 3rd trimester (0.76-fold) and cefazolin in the 2nd trimester (1.27-fold). Overall, we successfully predicted clearances of drugs in pregnancy that are renally secreted by multiple OATs. This approach could be used in the future to adjust dosing regimens of renally secreted OAT drugs which are administered to pregnant women. Significance Statement To our knowledge, this is the first report to successfully predict renal secretory clearance and renal clearance of multiple OAT-substrate drugs during pregnancy. The data presented here could be used in the future to adjust dosing regimens of renally secreted OAT drugs in pregnancy. In addition, the mechanistic approach used here could be extended to drugs transported by other renal transporters.