Identification and quantitation of mifepristone and its N-demethyl metabolite in the plasma of an aborted fetus by liquid chromatography–quadrupole–time-of-flight–mass spectrometry (LC–Q–TOFMS) and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS–MS)

Ishii, Akira; Zaitsu, Kei; Kusano, Maiko; Asano, Tomomi; Ogawa, Tadashi; Hattori, Hideki; Seno, Hiroshi

doi:10.1007/s11419-015-0284-7

Cited by 3 publications

(5 citation statements)

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“…The dose of RU486 used clinically in this study, however, was 200 mg/patient (average 2.7 mg/kg), which is less than the dose required for anti-glucocorticoid action (4.5 mg/kg) [ 47 ]. Furthermore, while RU486 transfers readily across the placenta, fetal plasma concentrations of the drug are 0.1–10% of those found in the maternal circulation [ 48 , 49 ], and it is highly unlikely that fetal drug concentrations will reach the threshold levels required to affect the fetal HPA axis. This is borne out by an earlier study which reported that use of RU486 during terminations (at 600 mg, three times the dose used in this study) had no effect on fetal or maternal plasma cortisol concentrations [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester

Johnston

Bellingham

Filis

et al. 2018

BMC Med

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BackgroundHuman fetal adrenal glands are highly active and, with the placenta, regulate circulating progesterone, estrogen and corticosteroids in the fetus. At birth the adrenals are essential for neonate salt retention through secretion of aldosterone, while adequate glucocorticoids are required to prevent adrenal insufficiency. The objective of this study was to carry out the first comprehensive analysis of adrenal steroid levels and steroidogenic enzyme expression in normal second trimester human fetuses.MethodsThis was an observational study of steroids, messenger RNA transcripts and proteins in adrenals from up to 109 second trimester fetuses (11 weeks to 21 weeks) at the Universities of Aberdeen and Glasgow. The study design was balanced to show effects of maternal smoking.ResultsConcentrations of 19 intra-adrenal steroids were quantified using liquid chromatography and mass spectrometry. Pregnenolone was the most abundant steroid while levels of 17α-hydroxyprogesterone, dehydroepiandrosterone sulphate (DHEAS) and progesterone were also high. Cortisol was present in all adrenals, but aldosterone was undetected and Δ4 androgens were low/undetected. CYP17A1, CYP21A2 and CYP11A1 were all highly expressed and the proteins localized to the adrenal fetal zone. There was low-level expression of HSD3B and CYP11B2, with HSD3B located mainly in the definitive zone. Maternal smoking altered fetal plasma adrenocorticotropic hormone (ACTH) (P = 0.052) and intra-adrenal progesterone, 17α-hydroxyprogesterone and 16α-hydroxyprogesterone, but not plasma or intra-adrenal cortisol, or intra-adrenal DHEAS. Fetal adrenal GATA6 and NR5A1 were increased by maternal smoking.ConclusionsThe human fetal adrenal gland produces cortisol but very low levels of Δ4 androgens and no detectable aldosterone throughout the second trimester. The presence of cortisol in fetal adrenals suggests that adrenal regulation of circulating fetal ACTH remains a factor in development of congenital adrenal hyperplasia during the second trimester, while a relative lack of aldosterone explains the salt-wasting disorders frequently seen in extreme pre-term neonates. Finally, maternal smoking may alter fetal adrenal sensitivity to ACTH, which could have knock-on effects on post-natal health.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1009-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester

Johnston

Bellingham

Filis

et al. 2018

BMC Med

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“…Table 4 presents a comparison of LC methods for the determination of mifepristone in biological materials. It can be concluded that the method presented in this paper is characterized by the lowest limit of quantification, except for the method developed by Ishii et al [ 15 ]. However, in the abovementioned paper the validation results of the method were not provided.…”

Section: Resultsmentioning

confidence: 91%

“…The only study in which the mifepristone concentration in biological specimens after an illegal abortion was provided, is the paper by Ishii et al [ 15 ]. Mifepristone’s concentration in the fetal plasma sample was estimated to be 7.1 ng/mL.…”

Section: Resultsmentioning

confidence: 99%

“…The analytical techniques for mifepristone quantification described to date were only applied for plasma and serum samples examination. Determination of mifepristone was possible by using a high-performance liquid chromatography (HPLC), most commonly with UV detection [ 10 , 11 , 12 , 13 ]; only two papers concern the use of more specific detectors such as mass spectrometry (MS) with triple quadrupole (QqQ) [ 14 ] or with quadrupole time-of-flight (QTOF) [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Determination of Mifepristone (RU-486) and Its Metabolites in Maternal Blood Sample after Pharmacological Abortion

Szpot

Wachełko²,

Zawadzki

2022

Molecules

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The aim of the study was the development and validation of the UHPLC-QqQ-MS/MS method for the determination of mifepristone in human blood as well as the identification and quantification of its metabolites after self-induced pharmacological abortion. The metabolic pathway in humans was proposed after examination of an authentic casework. The fast and simple preanalytical procedure was successfully applied (pH9, tert-butyl-methyl ether). The validation parameters of the method were as follows: limit of quantification: 0.5 ng/mL; coefficients of determination: >0.999 (R2), intra- and inter-day accuracy and precision values did not exceed ± 13.2%. The recovery and matrix effect were in the range of 96.3–114.7% and from −3.0 to 14.7%, respectively. Toxicological analysis of the mother’s blood (collected the day after the pregnancy termination) revealed the presence of five compounds: mifepristone (557.4 ng/mL), N-desmethyl-mifepristone (638.7 ng/mL), 22-OH-mifepristone (176.9 ng/mL), N,N-didesmethyl-mifepristone (144.5 ng/mL) and N-desmethyl-hydroxy-mifepristone (qualitatively). To our knowledge, the study presented in this paper is the first report on the concentrations of mifepristone and its metabolites in maternal blood samples after performing a self-induced abortion. The established UHPLC-QqQ-MS/MS method is suitable for forensic toxicological analysis as well as in terms of clinical toxicology in future investigations (examination of pharmacokinetics, bioavailability and metabolism of RU-486).

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“…There was no method reported to quantify Mifepristone by HPLC. However, a fresh method has been created for estimating Mifepristone that is accurate, specific, precise, and repeatable [14][15][16].…”

Section: Abortionmentioning

confidence: 99%

Analytical Method Development and Validation for Estimation of Mifepristone in Pure and Pharmaceutical Dosage Form

Bastia

Gawade

Chopade³

et al. 2021

JPRI

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Mifepristone structurally belongs to the class of anti-progesterone steroids, which are used as an oral contraceptive. The reverse phase HPLC method was designed in a simplified and rapid way for the estimation of Mifepristone in bulk as well as tablets. The method was established using a Kromasil C18 column of dimensions of 250mm×4.6mm and a particle size of 5m.The used mobile phase was Acetonitrile: Water (70:30, v/v). The pump was pumped at 1 ml/min at a temperature of about 30 ± 2 °C and the eluted analyte was identified at 305 nm. Mifepristone eluted with a mean retention time of 6.27 minutes. The intended method was validated as per ICH (International Council for Harmonisation) guidelines, indicating a high degree of specificity, system suitability, accuracy, precision, and robustness. The LOD (Limit of detection) was found to be 0.7238 ppm and the limit of measurement was 0.9562 ppm. The method linearity was found to be between 1-6µg/ml, with an R2 of 0.9923. In accuracy studies, the percent recovery was found to be between 99.39% - 100.50%. The method was discovered to be precise as the values of the percent RSD were found to be less than 2.0% for both intraday and interday. The method was discovered to be reliable and robust. Mifepristone in marketed pharmaceutical tablet dosage form was effectively quantified using the established Reverse Phase HPLC method.

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Identification and quantitation of mifepristone and its N-demethyl metabolite in the plasma of an aborted fetus by liquid chromatography–quadrupole–time-of-flight–mass spectrometry (LC–Q–TOFMS) and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS–MS)

Cited by 3 publications

References 23 publications

The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester

The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester

Determination of Mifepristone (RU-486) and Its Metabolites in Maternal Blood Sample after Pharmacological Abortion

Analytical Method Development and Validation for Estimation of Mifepristone in Pure and Pharmaceutical Dosage Form

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