Characterization of Renal OAT3 and Hepatic CYP3A Activities in Pregnant Women with Acute Pyelonephritis Using the Endogenous Biomarker Cortisol and 6β-Hydroxycortisol.

This study evaluates the impact of acute pyelonephritis in pregnant women on the in vivo activity of renal OAT3 using the endogenous biomarker (EB) 6β-hydroxycortisol (6β-OHF) renal clearance (CL 6β-OHF) and AUC validated by correlating with the secretion clearance (CL) of the probe drug furosemide. Additionally, 6β-OHF formation clearance (CL 6β-OHF) as well as urinary (Ae/Ae) and plasma (AUC/AUC) ratios were also evaluated as EB for hepatic CYP3A activity. Pregnant women in their third trimester of gestation, diagnosed with acute pyelonephritis, were recruited before (pre-treatment, n = 8) and after (post-treatment, n = 8) cefuroxime treatment and resolution of acute pyelonephritis. All participants received a single dose of furosemide 40 mg for evaluation of OAT3 in vivo activity on both occasions followed by collection of urine and serial blood samples for 24 h. The CL 6β-OHF (geometric mean and 95% CI) increased from 1.81 L/h (0.86-3.83) to 11.82 L/h (6.58-21.24), whereas the AUC decreased from 44.85 ng h/mL (30.96-64.98) to 24.20 ng h/mL (16.05-36.48) pre- and post-treatment. Significant statistical correlations were observed between furosemide CL and CL 6β-OHF (R = 0.88, P = .01) and AUC (R = -0.66, P > .001). Additionally, the CL 6β-OHF was lower in pre-treatment 26.81 L/h (10.18-70.59) than in post-treatment 96.18 L/h (64.21-144.09), whereas AUC/AUC ratios were decreased from 0.014 (0.010-0.019) pre-treatment to 0.009 (0.006-0.013) post-treatment. Regarding Ae/Ae ratios, no differences were observed between pre-treatment and post-treatment. In conclusion, CL 6β-OHF evaluates renal OAT3 activity when CYP3A is inhibited, whereas CL 6β-OHF evaluates hepatic CYP3A when OAT3 is inhibited, such as in pregnant women with acute pyelonephritis.