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

IF 2.9 4区医学 Journal of Clinical Pharmacology Pub Date : 2025-01-13 DOI:10.1002/jcph.6186

João Paulo Bianchi Ximenez, Jhohann Richard de Lima Benzi, Julia Cristina Colombari, Matheus de Lucca Thomaz, Adriana Rocha, Ana Cláudia Rabelo E Silva, Patrícia Pereira Dos Santos Melli, Geraldo Duarte, Vera Lucia Lanchote

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Abstract

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_renal 6β-OHF) and AUC_6β-OHF validated by correlating with the secretion clearance (CL_sec) of the probe drug furosemide. Additionally, 6β-OHF formation clearance (CL_formation 6β-OHF) as well as urinary (Ae_6β-OHF/Ae_F) and plasma (AUC_6βOHF/AUC_F) 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_renal 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_6β-OHF 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_sec and CL_renal 6β-OHF (R = 0.88, P = .01) and AUC_6β-OHF (R = -0.66, P > .001). Additionally, the CL_formation 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_6βOHF/AUC_F ratios were decreased from 0.014 (0.010-0.019) pre-treatment to 0.009 (0.006-0.013) post-treatment. Regarding Ae_6β-OHF/Ae_F ratios, no differences were observed between pre-treatment and post-treatment. In conclusion, CL_renal 6β-OHF evaluates renal OAT3 activity when CYP3A is inhibited, whereas CL_formation 6β-OHF evaluates hepatic CYP3A when OAT3 is inhibited, such as in pregnant women with acute pyelonephritis.

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内源性生物标志物皮质醇和6β-羟基皮质醇对急性肾盂肾炎孕妇肾脏OAT3和肝脏CYP3A活性的影响

本研究利用内源性生物标志物（EB） 6β-羟基皮质醇（6β-OHF）肾清除率（CLrenal 6β-OHF）和AUC6β-OHF，通过与探针药物速尿的分泌清除率（CLsec）相关验证，评估孕妇急性肾盂肾炎对肾脏OAT3体内活性的影响。此外，6β-OHF形成清除率（CLformation 6β-OHF）以及尿液（Ae6β-OHF/AeF）和血浆（AUC6βOHF/AUCF）比率也被评估为肝脏CYP3A活性的EB。在头孢呋辛治疗急性肾盂肾炎消退前（治疗前，n = 8）和治疗后（治疗后，n = 8）招募诊断为急性肾盂肾炎的妊娠晚期孕妇。所有参与者均接受单剂量速尿40 mg用于评估OAT3体内活性，随后收集尿液和连续血液样本24小时。CLrenal 6- β- ohf（几何平均值和95% CI）从1.81 L/h（0.86-3.83）增加到11.82 L/h(6.58-21.24)，而auc6 - β- ohf从44.85 ng h/mL（30.96-64.98）下降到24.20 ng h/mL（16.05-36.48）。速尿CLsec与CLrenal 6β-OHF （R = 0.88, P = 0.01）、AUC6β-OHF （R = -0.66, P = 0.001）具有显著的统计学相关性。CLformation 6- β- ohf在处理前26.81 L/h（10.18 ~ 70.59）低于处理后96.18 L/h(64.21 ~ 144.09)，而auc6 - β ohf /AUCF比值由处理前0.014（0.010 ~ 0.019）降至处理后0.009（0.006 ~ 0.013）。Ae6β-OHF/AeF比值处理前后无差异。综上所述，当CYP3A被抑制时，CLrenal 6 - β- ohf评估肾脏OAT3活性，而当OAT3被抑制时，CLformation 6 - β- ohf评估肝脏CYP3A活性，如急性肾盂肾炎孕妇。

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Journal of Clinical Pharmacology PHARMACOLOGY & PHARMACY-

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3.40%

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期刊介绍： The Journal of Clinical Pharmacology (JCP) is a Human Pharmacology journal designed to provide physicians, pharmacists, research scientists, regulatory scientists, drug developers and academic colleagues a forum to present research in all aspects of Clinical Pharmacology. This includes original research in pharmacokinetics, pharmacogenetics/pharmacogenomics, pharmacometrics, physiologic based pharmacokinetic modeling, drug interactions, therapeutic drug monitoring, regulatory sciences (including unique methods of data analysis), special population studies, drug development, pharmacovigilance, womens’ health, pediatric pharmacology, and pharmacodynamics. Additionally, JCP publishes review articles, commentaries and educational manuscripts. The Journal also serves as an instrument to disseminate Public Policy statements from the American College of Clinical Pharmacology.