João Paulo Bianchi Ximenez PhD, Jhohann Richard de Lima Benzi PhD, Julia Cristina Colombari MA, Matheus de Lucca Thomaz MA, Adriana Rocha PhD, Ana Cláudia Rabelo e Silva MA, Patrícia Pereira dos Santos Melli MD, Geraldo Duarte PhD, MD, Vera Lucia Lanchote PhD
{"title":"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","authors":"João Paulo Bianchi Ximenez PhD, Jhohann Richard de Lima Benzi PhD, Julia Cristina Colombari MA, Matheus de Lucca Thomaz MA, Adriana Rocha PhD, Ana Cláudia Rabelo e Silva MA, Patrícia Pereira dos Santos Melli MD, Geraldo Duarte PhD, MD, Vera Lucia Lanchote PhD","doi":"10.1002/jcph.6186","DOIUrl":null,"url":null,"abstract":"<p>This study evaluates the impact of acute pyelonephritis in pregnant women on the <i>in vivo</i> activity of renal OAT3 using the endogenous biomarker (EB) 6β-hydroxycortisol (6β-OHF) renal clearance (CL<sub>renal</sub> 6β-OHF) and AUC<sub>6β-OHF</sub> validated by correlating with the secretion clearance (CL<sub>sec</sub>) of the probe drug furosemide. Additionally, 6β-OHF formation clearance (CL<sub>formation</sub> 6β-OHF) as well as urinary (Ae<sub>6β-OHF</sub>/Ae<sub>F</sub>) and plasma (AUC<sub>6βOHF</sub>/AUC<sub>F</sub>) 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 <i>in vivo</i> activity on both occasions followed by collection of urine and serial blood samples for 24 h. The CL<sub>renal</sub> 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<sub>6β-OHF</sub> 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<sub>sec</sub> and CL<sub>renal</sub> 6β-OHF (R = 0.88, <i>P</i> = .01) and AUC<sub>6β-OHF</sub> (R = −0.66, <i>P</i> > .001). Additionally, the CL<sub>formation</sub> 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<sub>6βOHF</sub>/AUC<sub>F</sub> ratios were decreased from 0.014 (0.010-0.019) pre-treatment to 0.009 (0.006-0.013) post-treatment. Regarding Ae<sub>6β-OHF</sub>/Ae<sub>F</sub> ratios, no differences were observed between pre-treatment and post-treatment. In conclusion, CL<sub>renal</sub> 6β-OHF evaluates renal OAT3 activity when CYP3A is inhibited, whereas CL<sub>formation</sub> 6β-OHF evaluates hepatic CYP3A when OAT3 is inhibited, such as in pregnant women with acute pyelonephritis.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"556-563"},"PeriodicalIF":0.0000,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Characterization of Renal OAT3 and Hepatic CYP3A Activities in Pregnant Women with Acute Pyelonephritis Using the Endogenous Biomarker Cortisol and 6β-Hydroxycortisol\",\"authors\":\"João Paulo Bianchi Ximenez PhD, Jhohann Richard de Lima Benzi PhD, Julia Cristina Colombari MA, Matheus de Lucca Thomaz MA, Adriana Rocha PhD, Ana Cláudia Rabelo e Silva MA, Patrícia Pereira dos Santos Melli MD, Geraldo Duarte PhD, MD, Vera Lucia Lanchote PhD\",\"doi\":\"10.1002/jcph.6186\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>This study evaluates the impact of acute pyelonephritis in pregnant women on the <i>in vivo</i> activity of renal OAT3 using the endogenous biomarker (EB) 6β-hydroxycortisol (6β-OHF) renal clearance (CL<sub>renal</sub> 6β-OHF) and AUC<sub>6β-OHF</sub> validated by correlating with the secretion clearance (CL<sub>sec</sub>) of the probe drug furosemide. Additionally, 6β-OHF formation clearance (CL<sub>formation</sub> 6β-OHF) as well as urinary (Ae<sub>6β-OHF</sub>/Ae<sub>F</sub>) and plasma (AUC<sub>6βOHF</sub>/AUC<sub>F</sub>) 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 <i>in vivo</i> activity on both occasions followed by collection of urine and serial blood samples for 24 h. The CL<sub>renal</sub> 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<sub>6β-OHF</sub> 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<sub>sec</sub> and CL<sub>renal</sub> 6β-OHF (R = 0.88, <i>P</i> = .01) and AUC<sub>6β-OHF</sub> (R = −0.66, <i>P</i> > .001). Additionally, the CL<sub>formation</sub> 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<sub>6βOHF</sub>/AUC<sub>F</sub> ratios were decreased from 0.014 (0.010-0.019) pre-treatment to 0.009 (0.006-0.013) post-treatment. Regarding Ae<sub>6β-OHF</sub>/Ae<sub>F</sub> ratios, no differences were observed between pre-treatment and post-treatment. In conclusion, CL<sub>renal</sub> 6β-OHF evaluates renal OAT3 activity when CYP3A is inhibited, whereas CL<sub>formation</sub> 6β-OHF evaluates hepatic CYP3A when OAT3 is inhibited, such as in pregnant women with acute pyelonephritis.</p>\",\"PeriodicalId\":22751,\"journal\":{\"name\":\"The Journal of Clinical Pharmacology\",\"volume\":\"65 5\",\"pages\":\"556-563\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-01-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Clinical Pharmacology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jcph.6186\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Clinical Pharmacology","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jcph.6186","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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 (CLrenal 6β-OHF) and AUC6β-OHF validated by correlating with the secretion clearance (CLsec) of the probe drug furosemide. Additionally, 6β-OHF formation clearance (CLformation 6β-OHF) as well as urinary (Ae6β-OHF/AeF) and plasma (AUC6βOHF/AUCF) 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 CLrenal 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 AUC6β-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 CLsec and CLrenal 6β-OHF (R = 0.88, P = .01) and AUC6β-OHF (R = −0.66, P > .001). Additionally, the CLformation 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 AUC6βOHF/AUCF ratios were decreased from 0.014 (0.010-0.019) pre-treatment to 0.009 (0.006-0.013) post-treatment. Regarding Ae6β-OHF/AeF ratios, no differences were observed between pre-treatment and post-treatment. In conclusion, CLrenal 6β-OHF evaluates renal OAT3 activity when CYP3A is inhibited, whereas CLformation 6β-OHF evaluates hepatic CYP3A when OAT3 is inhibited, such as in pregnant women with acute pyelonephritis.
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