Toxicokinetic evaluation during intoxication of psychotropic drugs using brain microdialysis in mice

Inoue, Yumiko; Kaizaki-Mitsumoto, Asuka; Numazawa, Satoshi

doi:10.2131/jts.47.99

Cited by 4 publications

(6 citation statements)

References 29 publications

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“…Due to an insufficient number of mice at 24 hr post-administration, statistical analysis could not be conducted. Based on the above results and those of a previous study (Inoue et al, 2022) on FNZ singledrug administration, it is postulated that concurrent CPZ administration or an escalation in CPZ dosage leads to a prolongation of FNZ serum T1/2. Nevertheless, the Cmax and AUC 0-24h in both serum and brain remained unaffected, implying that the combination with CPZ is unlikely to enhance the effects of FNZ.…”

Section: Tk Parameters For Fnzsupporting

confidence: 60%

“…Consequently, for the present study, a severe toxic dose of 90 mg/kg of CPZ was selected. The LD50 value of FNZ is reported to be 1050 mg/kg (Miyagawa et al, 1985), but the sub-intoxication dose was set at 200 mg/kg because of its solubility (Inoue et al, 2022).…”

Section: Drug Treatmentmentioning

confidence: 99%

“…These doses were administered both independently and in combination with FNZ at a fixed dosage of 200 mg/kg. Toxicokinetics during FNZ single-drug administration were previously investigated in a study conducted by Inoue et al, 2022. In adherence to the 3R principle, FNZ single-drug administration was omitted in the present study.…”

Section: Toxicokinetics (Tk) Of Cpz and Fnzmentioning

confidence: 99%

“…FNZ boasts a wide safety margin based on its LD50/ED50 ratio and, in fact, has low lethal toxicity in single-drug overdoses. Our previous mouse model study demonstrated relatively mild increases of FNZ in blood and brain concentrations with escalating doses and low central toxicity in overdose situations (Inoue et al, 2022). However, FNZ abuse has prompted regulatory measures in many countries, including the United States and Europe (Saum and Inciardi, 1997;Victorri-Vigneau et al, 2003).…”

Section: Introductionmentioning

confidence: 98%

“…Given the pivotal role of brain drug levels in the manifestation of acute intoxication symptoms induced by CNS-acting drugs, elucidating the relationship between brain and blood drug levels is imperative. Our prior research involved characterizing the pharmacokinetic parameters of CNS drugs in mice, focusing on changes in brain concentrations following an overdose of a single drug (Inoue et al, 2022). It is crucial to recognize that even drugs that are safe when overdosed as single agents the toxicity of certain drugs may escalate when combined with others.…”

Section: Introductionmentioning

confidence: 99%

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Flunitrazepam alters the toxicokinetics of chlorpromazine enhancing its toxicity

Nakajima,

Kaizaki-Mitsumoto,

Numazawa

2023

Fundam. Toxicol. Sci.

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Flunitrazepam, a highly potent benzodiazepines, has a wide safety margin and widely used for insomnia treatment. However, a number of fatal poisoning cases involving a combination of flunitrazepam and other drugs have been reported. In instances of drug overdose deaths involving flunitrazepam in Japan, antipsychotic drugs like chlorpromazine are frequently used concomitantly. This study seeks to elucidate the pharmacokinetic interactions during the overdose of concurrent drugs, with a specific focus on the toxic effects of elevated doses of flunitrazepam and chlorpromazine in mice. Male ICR mice were intraperitoneally administered chlorpromazine (90 mg/kg) and flunitrazepam (200 mg/kg) either alone or concurrently. Body temperature was measured up to 24 hr after administration, and the number of deaths within 24 hr was quantified for each group. Additionally, flunitrazepam, chlorpromazine, and its active metabolite 7-hydroxychlorpromazine concentrations in serum and brain extracellular fluid were measured up to 24 hr after administration. Flunitrazepam enhanced the hypothermic effect of chlorpromazine, and acute intoxication deaths occurred only in the combination group. Cmax and AUC 0-24h of flunitrazepam in serum and brain were not affected by concomitant administration with chlorpromazine. While flunitrazepam significantly increased the AUC 0-24h of chlorpromazine, and the Cmax and AUC 0-24h of 7-hydroxychlorpromazine in serum. Flunitrazepam was shown to alter the toxicokinetics of chlorpromazine when administered in combination, thereby augmenting the toxicity of chlorpromazine and leading to lethal drug intoxication. This study underscores the significance of comprehending toxicokinetics not only for individual agents but also when utilized in combination.

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Section: Tk Parameters For Fnzsupporting

confidence: 60%

Section: Drug Treatmentmentioning

confidence: 99%

Section: Toxicokinetics (Tk) Of Cpz and Fnzmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Flunitrazepam alters the toxicokinetics of chlorpromazine enhancing its toxicity

Nakajima,

Kaizaki-Mitsumoto,

Numazawa

2023

Fundam. Toxicol. Sci.

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Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning

et al. 2023

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An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of phenobarbital in human serum and plasma

Schierscher,

Salzmann,

Singh

et al. 2024

Clinical Chemistry and Laboratory Medicine (CCLM)

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Objectives Phenobarbital serves as an antiepileptic drug (AED) and finds application in the treatment of epilepsy either as monotherapy or adjunctive therapy. This drug exhibits various pharmacodynamic properties that account for its beneficial effects as well as potential side effects. Accurate measurement of its concentration is critical for optimizing AED therapy through appropriate dose adjustments. Therefore, our objective was to develop and validate a new reference measurement procedure (RMP) for the accurate quantification of phenobarbital levels in human serum and plasma. Methods A sample preparation protocol based on protein precipitation followed by a high dilution step was established in combination with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using a C8 column to separate target analytes from known and unknown interferences. Assay validation and determination of measurement uncertainty were performed based on current guidelines. Selectivity and Specificity were assessed using spiked serum and plasma samples; to investigate possible matrix effects (MEs) a post-column infusion experiment and a comparison of standard line slopes was performed. Precision and accuracy were determined within a multiday precision experiment. Results The RMP was shown to be highly selective and specific, with no evidence of matrix interferences. It can be used to quantify phenobarbital in the range of 1.92 to 72.0 μg/mL. Intermediate precision was less than 3.2 %, and repeatability coefficient of variation (CV) ranged from 1.3 to 2.0 % across all concentration levels. The relative mean bias ranged from −3.0 to −0.7 % for native serum levels, and from −2.8 to 0.8 % for Li-heparin plasma levels. The measurement uncertainties (k=1) for single measurements and target value assignment were 1.9 to 3.3 % and 0.9 to 1.6 %, respectively. Conclusions A novel LC-MS/MS-based candidate RMP for the quantification of phenobarbital in human serum and plasma is presented which can be used for the standardization of routine assays and the evaluation of clinically relevant samples.

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Toxicokinetic evaluation during intoxication of psychotropic drugs using brain microdialysis in mice

Cited by 4 publications

References 29 publications

Flunitrazepam alters the toxicokinetics of chlorpromazine enhancing its toxicity

Flunitrazepam alters the toxicokinetics of chlorpromazine enhancing its toxicity

Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning

An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of phenobarbital in human serum and plasma

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