Lack of Modulation of In Vivo Activity of Organic Anion Transporters 1 and 3 in Pregnancy Using Furosemide as a Probe.

Pregnancy induces physiological changes that can alter drug disposition, yet little is known about their impact on renal transporters such as organic anion transporters 1 and 3 (OAT1/3). This study aimed to evaluate the in vivo activity of OAT1/3 during pregnancy using furosemide as a probe substrate. Twelve healthy non-pregnant women and 10 healthy pregnant women, mostly in the third trimester, received a single 40-mg oral dose of furosemide under fasting conditions. Serial blood and urine samples were collected for up to 24 h. Pharmacokinetic parameters were estimated by non-compartmental analysis, including time to maximum plasma concentration (tmax), maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), amount excreted in urine (Ae), fraction excreted unchanged in urine (fe), unbound plasma fraction (fu), apparent clearance (CL/F), renal clearance (CLR), non-renal clearance (CLNR), secretory clearance (CLSEC), and metabolic clearance via furosemide glucuronide formation (CLM). Compared with non-pregnant women, pregnant women exhibited significantly lower exposure, Cmax, Ae, and fe values, while CL/F and CLNR were significantly increased. In contrast, no significant differences were observed for CLR and CLSEC, indicating preserved OAT1/3 activity. These findings suggest unchanged OAT1/3-mediated renal secretory activity during pregnancy contrast with the published literature for other OAT1/3 substrates, which have, in most cases, reported an increase in OAT1/3 activity during pregnancy. Instead, the data raise the hypothesis that changes in intestinal absorption of furosemide, possibly influenced by gestational regulation of intestinal transporters, may contribute to the lower exposure.