Determination of metyrapone and the enantiomers of its chiral metabolite metyrapol in human plasma and urine using coupled achiral-chiral liquid chromatography

Chiarotto, James A.; Wainer, Irving W.

doi:10.1016/0378-4347(94)00500-5

Cited by 16 publications

(10 citation statements)

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“…The calibration concentration range was selected based on the works of Chiarotto and Wainer. 1,2 The following regression equations and correlation coefficients were obtained: y = −3426.3 + 1.23 × 10 -5 x (r = 0.998) for the (−)-enantiomer, y = −3085.4 + 1.22 × 10 -5 x (r = 0.999) for the (+)-enantiomer and y = −3437.2 + 1.06 × 10 -5 x (r = 0.999) for metyrapone.…”

Section: Resultsmentioning

confidence: 99%

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Determination of the plasma levels of metyrapone and its enantiomeric metyrapol metabolites by direct plasma injection and multidimensional achiral–chiral chromatography

et al. 2002

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The development and validation of a direct injection high-performance liquid chromatographic (HPLC) method, with column switching, for the determination of metyrapol enantiomers and metyrapone in human plasma is described. The system used in this work was composed of a restricted access media (RAM) bovine serum albumin (BSA) octyl column coupled to an amylose tris(3,5-dimethoxyphenylcarbamate) chiral column. Water was used as eluent for the first 5 min at a flow rate of 1.0 ml/min for the elution of the plasma proteins and then acetonitrile-water (30:70 v/v) for the transfer and analysis of metyrapol enantiomers and metyrapone, which were detected by UV at lambda = 260 nm. The total analysis time was about 32 min. The calibration curves for each enantiomer and for the metyrapone were linear in the ranges 0.075-0.75 microg/ml and 0.150-1.50 microg/ml, respectively. Recoveries, intra- and interday precision and accuracy were determined using three quality controls, one low (0.18 microg/ml), one medium (0.75 microg/ml), and one high (1.35 microg/ml) plasma concentration. Quantitative recoveries and good precision and accuracy were obtained. The limit of quantitation were 0.045 microg/ml for both enantiomers and for the metyrapone.

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Section: Resultsmentioning

confidence: 99%

“…A number of chromatographic procedures [1][2][3] have been published for the quantification of the enantiomers of metyrapol in the presence of metyrapone. All of them, however, were carried out by normal phase elution mode and used liquid-liquid or solid-liquid extraction prior to the analysis.…”

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Determination of the plasma levels of metyrapone and its enantiomeric metyrapol metabolites by direct plasma injection and multidimensional achiral–chiral chromatography

et al. 2002

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“…(). Metyrapone plasma concentrations were determined following a modified method of Chiarotto and Wainer (). Briefly, daily standard curves were fortified with metyrapone at 0, 25, 50, 100, 250 and 500 ng·mL −1 using 1 mL of blank plasma.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of MDMA‐induced increase in cortisol does not prevent acute impairment of verbal memory

Kuypers

Torre

Farré

et al. 2013

British J Pharmacology

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BackgroundEcstasy use is commonly linked with memory deficits in abstinent ecstasy users. Similar impairments are being found during ecstasy intoxication after single doses of ± 3,4 metylenedioxymethamphetamine (MDMA). The concordance of memory impairments during intoxication and abstinence suggests a similar neuropharmacological mechanism underlying acute and chronic memory impairments. The mechanism underlying this impairment is to date not known. We hypothesized that cortisol might play an important role in this mechanism as cortisol, implicated in the regulation of memory performance, can be brought out of balance by stressors like MDMA.MethodsIn the present study, we aimed to block the MDMA-induced acute memory defect by giving participants a cortisol synthesis inhibitor (metyrapone) together with a single dose of MDMA. Seventeen polydrug MDMA users entered this placebo-controlled within subject study with four treatment conditions. The treatments consisted of MDMA (75 mg) and metyrapone (750 mg), alone and in combination, and double placebo. Pre-treatment with metyrapone or Placebo occurred 1 h prior to MDMA or Placebo administration. Memory performance was tested at peak drug concentrations by means of several memory tests. Cortisol levels were determined in blood and oral fluid; this served as a control measure to see whether manipulations were effective.ResultsMain findings indicated that whereas treatment with metyrapone blocked the expected MDMA-induced increase in cortisol levels in blood, it did not prevent the MDMA-induced memory deficit from happening.ConclusionWe therefore conclude that MDMA-induced increments in cortisol concentrations are not related to MDMA-induced memory impairments.

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“…On intravenous infusion to leukaemic patients its plasma levels decrease rapidly and its reduced metabolite daunorubicinol attains 2-to 4-fold higher concentrations (Galettis et al 1994). With metyrapone, another good CR substrate (Ohara et al 1995), data on in-vivo kinetics are available for a single subject only; they reveal a large excess of the two metyrapol enantiomers over the parent drug in plasma as well as in urine (Chiarotto & Wainer 1995). Interestingly, carbonyl reduction has not been described as a biotransformation reaction in ondansetron, another ketonic 5-HT 3 receptor antagonist (Roila & Del Favero 1995).…”

Section: Discussionmentioning

confidence: 99%

Carbonyl reduction of naltrexone and dolasetron by oxidoreductases isolated from human liver cytosol

Breyer-Pfaff

Nill

2004

Journal of Pharmacy and Pharmacology

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The opioid receptor antagonist naltrexone and the antiemetic 5-HT(3) receptor antagonist dolasetron are ketonic drugs that are efficiently reduced to their corresponding alcohols in-vivo. These experiments aimed at characterizing the role in these reactions of individual oxidoreductases present in human liver cytosol. Aldo-keto reductases (AKRs) and carbonyl reductase (CR, EC 1.1.1.184) purified from human liver cytosol were incubated with varying substrate concentrations and 6beta-naltrexol or reduced dolasetron were analysed by HPLC. AKR1C1, AKR1C2, and AKR1C4 were able to reduce both substrates. On the basis of k(cat)/K(m) values, AKR1C4 was nearly 1000-fold more efficient in reducing naltrexone than was AKR1C1, while AKR1C2 was of intermediate efficiency. Substrate inhibition was observed on incubating AKR1C2 or AKR1C4 with naltrexone. In contrast, dolasetron was also a substrate of CR. AKR1C1 and AKR1C4 were the most efficient enzymes in producing reduced dolasetron. We concluded that the efficient reduction of naltrexone by AKR1C4 probably causes the high 6beta-naltrexol/naltrexone ratio in man. The rapid disappearance from human plasma of dolasetron given intravenously and its virtual absence after oral dosage are explained by its liability to reduction by several enzymes, including CR which shows widespread expression in human tissues.

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Determination of metyrapone and the enantiomers of its chiral metabolite metyrapol in human plasma and urine using coupled achiral-chiral liquid chromatography

Cited by 16 publications

References 6 publications

Determination of the plasma levels of metyrapone and its enantiomeric metyrapol metabolites by direct plasma injection and multidimensional achiral–chiral chromatography

Determination of the plasma levels of metyrapone and its enantiomeric metyrapol metabolites by direct plasma injection and multidimensional achiral–chiral chromatography

Inhibition of MDMA‐induced increase in cortisol does not prevent acute impairment of verbal memory

Carbonyl reduction of naltrexone and dolasetron by oxidoreductases isolated from human liver cytosol

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