HPLC determination of benzydamine and its metabolite N-oxide in plasma following oral administration or topical application in man, using fluorimetric detection

Catanese, B; Laganà, Aldo; Marino, Andrea; Picollo, Rossella; Rotatori, Mauro

doi:10.1016/0031-6989(86)90091-3

Cited by 20 publications

(9 citation statements)

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“…BZD N ‐demethylation is a second pathway of BZD metabolism ( Figure 1) that contibutes less than 10% to overall BZD degradation in human liver microsomes [15, 16]. Our data allowed a qualitative estimate regarding the enzymes involved in this pathway.…”

Section: Discussionmentioning

confidence: 99%

“…BZD is extensively metabolized, less than 1% of the parent drug is eliminated unchanged in the urine [17]. BZD‐NO is the major metabolite in vivo with peak plasma concentrations of approximately 200 ng ml −1 [16].…”

Section: Discussionmentioning

confidence: 99%

“…However, since exposure to this compound occurs from endogenous and exogenous sources, partial metabolic clearances via FMO3 cannot be precisely measured using trimethylamine‐ N ‐oxidation. Benzydamine (BZD) is a nonsteroidal antiinflammatory drug extensively metabolized to benzydamine N ‐oxide (BZD‐NO) ( Figure 1), the major metabolite found in plasma and urine of human subjects [15–17]. Previous studies demonstrated that N ‐oxidation is the major pathway of BZD biotransformation in various species in vitro and in situ [18, 19].…”

Section: Introductionmentioning

confidence: 87%

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Benzydamine N‐oxidation as an index reaction reflecting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity

Störmer

Roots

Brockmöller

2000

Brit J Clinical Pharma

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Aims The role of¯avin containing monooxygenases (FMO) on the disposition of many drugs has been insuf®ciently explored. In vitro and in vivo tests are required to study FMO activity in humans. Benzydamine (BZD) N-oxidation was evaluated as an index reaction for FMO as was the impact of genetic polymorphisms of FMO3 on activity.Methods BZD was incubated with human liver microsomes (HLM) and recombinant enzymes. Human liver samples were genotyped using PCR-RFLP. Results BZD N-oxide formation rates in HLM followed Michaelis-Menten kinetics (mean K m =64.0 mM, mean V max = 6.9 nmol mg x1 protein min x1 ; n=35). Nbenzylimidazole, a nonspeci®c CYP inhibitor, and various CYP isoform selective inhibitors did not affect BZD N-oxidation. In contrast, formation of BZD N-oxide was almost abolished by heat treatment of microsomes in the absence of NADPH and strongly inhibited by methimazole, a competitive FMO inhibitor. Recombinant FMO3 and FMO1 (which is not expressed in human liver), but not FMO5, showed BZD N-oxidase activity. Respective K m values for FMO3 and FMO1 were 40.4 mM and 23.6 mM, and respective V max values for FMO3 and FMO1 were 29.1 and 40.8 nmol mg x1 protein min x1 . Human liver samples (n=35) were analysed for six known FMO3 polymorphisms. The variants I66M, P135L and E305X were not detected. Samples homozygous for the K158 variant showed signi®cantly reduced V max values (median 2.7 nmol mg x1 protein min x1 ) compared to the carriers of at least one wild type allele (median 6.2 nmol mg x1 protein min x1 ) (P<0.05, Mann± Whitney-U-test). The V257M and E308G substitutions had no effect on enzyme activity. Conclusions BZD N-oxidation in human liver is mainly catalysed by FMO3 and enzyme activity is affected by FMO3 genotype. BZD may be used as a model substrate for human liver FMO3 activity in vitro and may be further developed as an in vivo probe re¯ecting FMO3 activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

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Benzydamine N‐oxidation as an index reaction reflecting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity

Störmer

Roots

Brockmöller

2000

Brit J Clinical Pharma

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“…There are a number of articles describing the quantitative determination of Benzydamine hydrochloride in the finished dosage forms by HPLC [4][5][6]. Separation of Benzydamine is described with utilization of RP-phase with fluorescence or spectrophotometric detec-tion in either finished dosage forms or blood samples.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of the method for simultaneous determination of Benzydamine hydrochloride and methylparaben in dosage form by HPLC

Chornyi¹,

Chorna²,

Georgiyants³

2020

ScienceRise: Pharmaceutical Science

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Мета дослідження. Метою даної роботи було розробити та затвердити метод ВЕРХ для одночасного визначення бензидаміну гідрохлориду (АФІ) та метилпарабену (консервант) у лікарській формі, що містить бензидамін гідрохлорид як активний фармацевтичний інгредієнт. Методи. Розділення проводили на колонці Grace Altima C18 (250*4,6 мм, розмір частинок 5 мкм). Рухома фаза складалася з 3,0 г перхлорату натрію, 1 мл триметиламіну і доводилася до рН 3 перхлорною кислотою. Швидкість потоку рухомої фази становила 1 мл / хв, довжина хвилі виявлення-320 нм для гідрохлориду бензидаміну та 254 нм для метилпарабену. Результати. Метод був перевірений відповідно до вимог ICH Q2 і визнаний надійним, специфічним, лінійним в діапазоні від 80 % до 120 % для аналізованої речовини. Максимальне RSD для кожного з'єднання становило менше 1.3 %. Точність методу була в межах критеріїв прийнятності. Висновки. Метод одночасного визначення бензидаміну гідрохлориду та метилпарабену був розроблений і затверджений відповідно до вимог Міжнародної конференції з гармонізації. Всі параметри валідації відповідають критеріям прийнятності керівництва. Розроблений метод може бути застосований в рутинному контролі в лабораторіях контролю якості для одночасного визначення бензидаміну гідрохлориду та метилпарабену в лікарських формах бензидаміну.

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“…Literature studies of vaginal benzydamine douches demonstrated their safety and a low rate of systemic absorption [29]. Following a single intravaginal application, only a minimal percentage of the drug was detectable in plasma, compared to vaginal mucosa [29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Phase I Study in Healthy Women of a Novel Antimycotic Vaginal Ovule Combining Econazole and Benzydamine

Stefano¹,

Radicioni²,

Vaccani³

et al. 2020

Infectious Diseases in Obstetrics and Gynecology

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Purpose. A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulated in vaginal ovules was investigated in a randomised, double-blind, four-parallel group, tolerability, and pharmacokinetic Phase I study in healthy women. Methods. The fixed-dose combination was compared to econazole and benzydamine single-drug formulations and with placebo after daily applications for 3 consecutive days. Safety and tolerability were evaluated recording the adverse drug reactions, local and general tolerability scores, clinical laboratory assays, and vital signs. Econazole, benzydamine, and its metabolite benzydamine N-oxide pharmacokinetics were investigated after single and multiple applications. Results. Local reactions were generally absent. Pruritus and pain at the application site were infrequently reported. According to the subjects’ evaluations, the overall tolerability of the ovules was rated as excellent or good. No significant effect of any treatment on laboratory parameters, vital signs, body weight, vaginal pH, or ECG was observed. Very low econazole, benzydamine, and benzydamine-N-oxide concentrations were measured in plasma, though quantifiable in almost all samples. Conclusion. The tested fixed-dose combination showed a good safety profile consistently with the known tolerability of both active substances. In addition, the confirmed low bioavailability of the drugs excludes the possibility of any accumulation effects and limits the risk of undesired systemic effects. This trial is registered at ClinicalTrials.gov with the identifier NCT02720783 last updated on 07 February 2017.

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HPLC determination of benzydamine and its metabolite N-oxide in plasma following oral administration or topical application in man, using fluorimetric detection

Cited by 20 publications

References 2 publications

Benzydamine N‐oxidation as an index reaction reflecting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity

Benzydamine N‐oxidation as an index reaction reflecting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity

Development and validation of the method for simultaneous determination of Benzydamine hydrochloride and methylparaben in dosage form by HPLC

Phase I Study in Healthy Women of a Novel Antimycotic Vaginal Ovule Combining Econazole and Benzydamine

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