A developed determination of midazolam and 1′-hydroxymidazolam in plasma by liquid chromatography–mass spectrometry: Application of human pharmacokinetic study for measurement of CYP3A activity

Shimizu, Mikiko; Uno, Tsukasa; Tamura, Hiro Omi; Kanazawa, Hideko; Murakami, Isao; Sugawara, Kazunobu; Tateishi, Tetsuya

doi:10.1016/j.jchromb.2006.10.018

Cited by 30 publications

(19 citation statements)

References 32 publications

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“…This approach provides for the preservation of data structure so that each individual condition contributes to the population description. The model estimate of clearance of midazolam was 18.5 l/h at 36.5°C, which was consistent with previous studies (Bolon et al, 2003;de Wildt et al, 2003;Shimizu et al, 2007). The relationship between core body temperature and the midazolam systemic clearance was described using the function, CL (liters per hour) ϭ 18.5 ϫ (TEM/36.5) 4.24 , which provided the basis for predicting the temperature relationship with clearance of midazolam.…”

Section: Pharmacokinetic Variables For Four Treatments From Noncomparsupporting

confidence: 86%

Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

et al. 2010

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ABSTRACT:The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, which included two mild hypothermia groups (4°C saline infusions and 4°C saline ؉ magnesium) and two normothermia groups (37°C saline infusions and 37°C saline ؉ magnesium). The lowest temperatures achieved in the 4°C saline ؉ magnesium and 4°C saline infusions were 35.4 ؎ 0.4 and 35.8 ؎ 0.3°C, respectively. A significant decrease in the formation clearance of the major metabolite 1-hydroxymidazolam was observed during the 4°C saline ؉ magnesium compared with that in the 37°C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5°C. Midazolam with magnesium facilitated the induction of hypothermia, but shivering was minimally suppressed. These data provided proof of concept that even mild and short-duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower levels and a longer duration of hypothermia are warranted.

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Section: Pharmacokinetic Variables For Four Treatments From Noncomparsupporting

confidence: 86%

Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

et al. 2010

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“…However, this approach compromises the cleanliness of the samples, and it is not economical due to damage to the column and potential contamination of the detector. Although liquid-liquid extraction produces cleaner plasma sample extracts, and it has been used successfully for quantification of midazolam and its two metabolites [21,24,25], as well as fentanyl and norfentanyl in plasma samples [19], it is an expensive and labour intensive method using very toxic solvents such as toluene for fentanyl, norfentanyl [19] and midazolam [25], ethyl acetate for morphine and its glucuronide metabolites [26], or hexane for midazolam [21,24].…”

Section: Methods Development For Lc and On-line Spementioning

confidence: 99%

“…For example, although midazolam is a widely used sedative hypnotic drug, it is also used as a probe compound for measuring CYP3A enzyme activity in in vivo phenotyping studies in humans. For phenotyping studies, an LLOQ of 0.1 ng/mL is required that is achieved by using a relatively large plasma volume and reconstitution in a much smaller volume of mobile phase prior to injection into the mass spectrometer [21,24,25]. Likewise, measurement of plasma fentanyl concentrations following administration by the transdermal route requires assays of much higher sensitivity than for applications involving the parenteral dosing route [17,18].…”

Section: Lower Limit Of Quantificationmentioning

confidence: 99%

“…Previously, separate LC-MS/MS assay methods for quantification of the plasma concentrations of morphine, M3G and M6G [9][10][11][12][13]; fentanyl and norfentanyl [14][15][16][17][18][19]; midazolam, 1-OH-MDZ and 4-OH-MDZ [20][21][22][23][24][25] have been described in the literature. Here, we have successfully extracted all eight of these analytes of interest from a single 150 L plasma sample using a single polymeric cartridge and on-line SPE with subsequent LC-MS/MS quantification.…”

Section: Introductionmentioning

confidence: 99%

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High-throughput assay for simultaneous quantification of the plasma concentrations of morphine, fentanyl, midazolam and their major metabolites using automated SPE coupled to LC–MS/MS

Ghassabian

Moosavi

Valero

et al. 2012

Journal of Chromatography B

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“…It is widely used as a premedication in children [Barkan et al, 2013]. Midazolam is primarily metabolized in the liver by the CYP3A (CYP3A4 in human) to its pharmacologic active metabolite, α-hydroxymidazolam [Shimizu et al, 2007]. Moreover, α-hydroxymidazolam potency is comparable with the parent drug and contributes to the overall effect of midazolam.…”

Section: Introductionmentioning

confidence: 99%

In vitro ketamine CYP3A‐mediated metabolism study using mammalian liver S9 fractions, cDNA expressed enzymes and liquid chromatography tandem mass spectrometry

Santamaria

Pailleux

Beaudry

2014

Biomedical Chromatography

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Ketamine is widely used in medicine in combination with several benzodiazepines including midazolam. The objectives of this study were to develop a novel HPLC-MS/SRM method capable of quantifying ketamine and norketamine using an isotopic dilution strategy in biological matrices and study the formation of norketamine, the principal metabolite of ketamine with and without the presence of midazolam, a well-known CYP3A substrate. The chromatographic separation was achieved using a Thermo Betasil Phenyl 100 x 2 mm column combined with an isocratic mobile phase composed of acetonitrile, methanol, water and formic acid (60:20:20:0.4) at a flow rate of 300 µL/min. The mass spectrometer was operating in selected reaction monitoring mode and the analytical range was set at 0.05-50 µM. The precision (%CV) and accuracy (%NOM) observed were ranging from 3.9-7.8 and 95.9.2-111.1% respectively. The initial rate of formation of norketamine was determined using various ketamine concentration and K m values of 18.4 µM, 13.8 µM and 30.8 µM for rat, dog and human liver S9 fractions were observed respectively. The metabolic stability of ketamine on liver S9 fractions was significantly higher in human (T 1/2 = 159.4 min) compared with rat (T 1/2 = 12.6 min) and dog (T 1/2 = 7.3 min) liver S9 fractions. Moreover significantly lower IC 50 and K i values observed in human compared with rat and dog liver S9 fractions. Experiments with cDNA expressed CYP3A enzymes showed the formation of norketamine is mediated by CYP3A but results suggest an important contribution from others isoenzymes, most likely CYP2C particularly in rat.3

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A developed determination of midazolam and 1′-hydroxymidazolam in plasma by liquid chromatography–mass spectrometry: Application of human pharmacokinetic study for measurement of CYP3A activity

Cited by 30 publications

References 32 publications

Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

High-throughput assay for simultaneous quantification of the plasma concentrations of morphine, fentanyl, midazolam and their major metabolites using automated SPE coupled to LC–MS/MS

In vitro ketamine CYP3A‐mediated metabolism study using mammalian liver S9 fractions, cDNA expressed enzymes and liquid chromatography tandem mass spectrometry

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