Human plasma metabolic profiles of benzydamine, a flavin-containing monooxygenase probe substrate, simulated with pharmacokinetic data from control and humanized-liver mice.

1. Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir. 2. Following oral administration of benzydamine (10 mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine. In contrast, in control and ganciclovir-treated TK-NOG mice, concentrations of demethyl benzydamine were slightly higher than those of benzydamine N-oxide. 3. Simulations of human plasma concentrations of benzydamine and its N-oxide were achieved using simplified physiologically based pharmacokinetic models based on data from control TK-NOG mice and from reported benzydamine concentrations after low-dose administration in humans. Estimated clearance rates based on data from humanized-liver and ganciclovir-treated TK-NOG mice were two orders magnitude high. 4. The pharmacokinetic profiles of benzydamine were different for control and humanized-liver TK-NOG mice. Humanized-liver mice are generally accepted human models; however, drug oxidation in mouse kidney might need to be considered when probe substrates undergo FMO-dependent drug oxidation in mouse liver and kidney.

Benzydamine metabolism in vivo is impaired in patients with deficiency of flavin-containing monooxygenase 3.

Flavin-containing monooxygenase 3 (FMO3) is an important hepatic enzyme for the detoxification of xenobiotics. The pharmacogenetic relevance of FMO3 deficiency has frequently been postulated from in vitro studies but has not yet been proven in vivo. We investigated the metabolism of benzydamine (BZD) in controls as well as patients with severe FMO3 deficiency and found evidence of markedly reduced N-oxygenation capacity both in serum and urine samples. After 2 h the N-oxide/total BZD ratio in serum of the patients ranged from 3.1 to 5.6% compared to controls with a median of 13.1%. Urinary BZD was almost fully N-oxygenated in controls (> 93.7%) whilst the urinary N-oxide/total BZD ratios were 29.4-35.7% in patients. Our study is the first to confirm that severe FMO3 deficiency is associated with reduced metabolism of a drug substrate in vivo. This is relevant because of the prevalence of mild FMO3 deficiency in the general population. BZD may be also useful as a diagnostic probe for determination of FMO3 deficiency in vivo.

Pharmacokinetics of benzydamine in dairy cows following intravenous or intramuscular administration.

Five lactating cows were given benzydamine hydrochloride by rapid intravenous (0.45 mg/kg) and by intramuscular (0.45 and 1.2 mg/kg) injection in a crossover design. The bioavailability, pharmacokinetic parameters and excretion in milk of benzydamine were evaluated. After intravenous administration, the disposition kinetics of benzydamine was best described using a two-compartment open model. Drug disposition and elimination were fast (t1/2 alpha: 11.13 +/- 3.76 min; t1/2 beta: 71.98 +/- 24.75 min; MRT 70.69 +/- 11.97 min). Benzydamine was widely distributed in the body fluids and tissues (Vd(area): 3.549 +/- 1.301 L/kg) and characterized by a high value for body clearance (33.00 +/- 5.54 ml/kg per min). After intramuscular administration the serum concentration-time curves fitted a one-compartment open model. Following a dose of 0.45 mg/kg, the Cmax value was 38.13 +/- 4.2 ng/ml at a tmax of 67.13 +/- 4.00 min; MAT and MRT were 207.33 +/- 22.64 min and 278.01 +/- 12.22 min, respectively. Benzydamine bioavailability was very high (92.07% +/- 7.08%). An increased intramuscular dose (1.2 mg/kg) resulted in longer serum persistence (MRT 420.34 +/- 86.39 min) of the drug, which was also detectable in milk samples collected from both the first and second milking after treatment.

Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects.

The pharmacokinetics of the anti-inflammatory drug benzydamine were determined after intravenous infusion of 5 mg to six healthy male subjects. Benzydamine was characterized as a drug of relatively low systemic clearance (ca. 160 ml min-1) but high volume of distribution (ca. 1101); the apparent terminal half-life in plasma was ca. 8 h. Benzydamine was well absorbed after oral administration, as indicated by a mean systemic availability of 87 per cent. However, absorption of the drug was low (less than 10 per cent of the dose) after its use by male subjects as a mouthwash, or after its application to female subjects as dermal cream and vaginal douche preparations. The data suggest that benzydamine is generally not well absorbed through the skin and non-specialized mucosae, thereby limiting unrequired systemic exposure to this drug when it is used by these routes.

Determination of benzydamine and its N-oxide in biological fluids by high-performance liquid chromatography.

A simple, sensitive and selective method for the determination of benzydamine in human plasma and urine, and for benzydamine N-oxide in urine, has been developed using high-performance liquid chromatography in the reversed-phase mode. The limit of reliable determination of benzydamine in plasma was 0.5 ng/ml and that in urine 1 ng/ml; the limit of reliable determination of benzydamine N-oxide in urine was 50 ng/ml. The method has been successfully applied to the analysis of these compounds in biological fluids after administration of intravenous and oral doses of benzydamine to human volunteers.

Determinaçäo dos efeitos das drogas antiinflamatórias näo esteróides (indometacina, butazona, clinoril, naprosin, benflogin e inflaril) nos leucogramas de ratos portadores de processo inflamatório crônico / Assessment of the effects of non-steroidal anti-inflammatory drugs (indomethacin, phenylbutazone, sulindac, naproxen, benzydamine and neflumic acid) on rat leucograms with chronic inflammatory process

Neste trabalho procurou-se avaliar os efeitos dos antiinflamatórios näo esteróides: Indometacina (indocid), Butazona (Fenilbutazona), Clinoril (Sulindac), Naprosin (Naproxen), Benflogin (Cloridrato de Benzidamina) e Inflaril (Acido neflúmico) nos leucogramas de ratos portadores de um processo inflamatório crônico provocado pela introduçäo intradérmica de lamínulas de vidro nos períodos de 3, 12 e 18 dias. O sangue para a contagem total dos leucócitos, eletrônica e diferencial, esfregaço, foi obtido por punçäo intracardíaca (Burhoe). A Indometacina, o Clinoril e a Butazona indicaram diminuiçäo de linfócitos e eosinófilos e aumento de monócitos e neutrófilos em todos os períodos e observaçäo em todos os períodos; o Inflaril reduziu o número de linfócitos, neutrofilia e eosinopenia em todos os períodos; o Inflaril reduziu o número de linfócitos e eosinófilos de aumentou os monócitos, com exceçäo de 3§ período, e os neutrófilos nos três períodos; e o Benflogin elevou os linfócitos na 1ª e 3ª fases, e os monócitos nos três períodos, e reduziu os neutrófilos nos dois primeiros, e os eosinfófilos nos dois últimos períodos. Todas as drogas usadas provocaram reduçäo de leucócitos em todos os períodos de tratamento, exceçäo feita ao Naprosin no 3§, ao Benflogin no 2§ e ao Inflaril no 1§ e 2§ períodos

Bioequivalence study of two liquid formulations of benzydamine.

A bioequivalence study of two liquid formulations containing benzydamine hydrochloride was carried out to evaluate the influence of a change of the excipients and the addition of a flavouring agent, ICEBERG AR 84/05/15, on the absorption of benzydamine. No statistically significant differences were observed suggesting that the two formulations are bioequivalent.

Concentration of benzydamine in vaginal mucosa following local application: an experimental and clinical study.

The results of an experimental and clinical study on the benzydamine binding and distribution in vaginal mucosa are presented, employing benzydamine solution for gynaecological use. When applied first to rats, the mean amount of the drug in their vaginal mucosa became 3.65 +/- 2.99 micrograms/g of fresh tissue with a significant difference between control and treated animals, without detectable amounts in the plasma. When applied to humans, the mean amount of benzydamine assayed in 17 specimens of vaginal mucosa was 9.72 +/- 6.24 micrograms/g. It was greater than the range of animal anti-inflammatory concentration (2-8 micrograms/g) established by pharmacological studies on this drug and justified the local benefits from benzydamine treatment of vaginal inflammation. Benzydamine assayed in seven volunteers with healthy vaginas showed that the drug cannot be detected in the plasma.

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

A method for the extraction and quantification of benzydamine and its metabolite N-oxide by liquid chromatography with fluorescence detection in plasma samples is described. This method has adequate sensitivity, specificity and is reproducible. The use of the extraction column allowed a recovery of both benzydamine and its metabolite of over 97% to be obtained. The plasma levels of benzydamine and its metabolite N-oxide were studied after oral administration as sugar-coated tablets or topical application to the vaginal mucosa as a cream to 6 healthy volunteers. After topical application, the plasma concentrations of the unchanged drug and its metabolite are lower than those obtained following oral administration. These data further stress the concept that, whenever possible, topical use should be considered the treatment of choice since, along with a more selective therapy, the incidence of systemic side effects can be considerably reduced.

Pharmacokinetics of benzydamine.

Clinically, benzydamine can exert its action locally or systemically. Consequently the pharmacokinetics of this drug have been studied after its administration by several different routes. Oral doses of benzydamine are apparently well absorbed and plasma drug concentrations reach a peak fairly rapidly (e.g. 0.8 micrograms/ml after a 100-mg dose) and then decline with a half-life of about 13 h. Less than 20% of the drug is bound to plasma proteins. Assuming complete oral systemic availability, values of 193 ml/min and 213 litres respectively were calculated for the systemic clearance and volume of distribution of benzydamine. Cutaneous doses of benzydamine are more slowly absorbed and lead to peak drug levels about three-fold lower, but more persistent than those after oral administration. Although local drug concentrations are relatively large, the systemic absorption of mouthwash-gargle, vaginal and rectal doses of benzydamine is relatively low compared to oral doses: this lower absorption should greatly diminish the potential for any systemic drug side-effects when benzydamine is administered by these routes. Benzydamine is metabolized primarily by oxidation, conjugation and dealkylation.

Serum levels of benzydamine following the topical use of this drug in gynecology.

The serum levels of benzydamine were studied after administration by vaginal douching (at a concentration of 0.0%) to patients with and without vaginal inflammation. In both experimental groups benzydamine produced similar serum concentrations which were lower than those obtained by other administration routes, excluding the possibillity of eventual systemic effects. These data are a further confirmation that, whenever possible, topical use is preferable to systemic use in order to reduce the incidence of systemic side effects to a minimum and to obtain a more selective therapy.