Kinetic characteristics and toxic effects of benzalkonium chloride following intravascular and oral administration in rats

Yang, Xue; Hieda, Yoko; Kimura, Kojiro; Takayama, Kōji; Fujihara, Junko; Tsujino, Yoshio

doi:10.1016/j.jchromb.2004.03.075

Cited by 18 publications

(2 citation statements)

References 24 publications

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“…Among the investigated polymers, PVP K90 was the most effective. BAK is a surfactant with a higher drug-solubilizing capacity, but SDS was chosen due to its lower toxicity [20]. Na 2 CO 3 provided the highest amount of dissolved DZ and was used as an alkalinizer to prepare SG-pHM and TG-pHM SDs.…”

Section: Resultsmentioning

confidence: 99%

Manufacturing Different Types of Solid Dispersions of BCS Class IV Polyphenol (Daidzein) by Spray Drying: Formulation and Bioavailability

et al. 2019

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Daidzein (DZ) is a polyphenolic compound belonging to Biopharmaceutical Classification System class IV, which shows that it may have limited therapeutic effects due to its low solubility and poor bioavailability. This study aimed to obtain high-purity DZ and prepare and characterize different types of solid dispersions (SDs) in order to enhance aqueous solubility and bioavailability. Excipients were investigated in order to manufacture different types of solid dispersions (SDs). Second-generation solid dispersions (SG), third-generation solid dispersions (TG), and second- and third-generation pH-modulated solid dispersions (SD and TG pHM-SD) were produced via spray drying. The SDs were characterized and tested for in vitro DZ release and oral bioavailability. SDs have shown increased aqueous solubility and in vitro release rate. Solid-state characterization showed that DZ was in an amorphous state in most of the formulations. The enhanced aqueous solubility of TG-pHM SD was reflected by an increase in oral bioavailability, which significantly increased the maximum plasma concentration approximately 20-fold and decreased the time to reach the maximum plasma concentration. The production of pHM SDs that contain DZ via spray drying is a simple and effective approach for oral drug delivery, which has the potential to greatly reduce the dose and enhance therapeutics effects.

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Section: Resultsmentioning

confidence: 99%

Manufacturing Different Types of Solid Dispersions of BCS Class IV Polyphenol (Daidzein) by Spray Drying: Formulation and Bioavailability

et al. 2019

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“…Single-dose intravenous injection of BACs to rats (7 mg/kg) led to a wide distribution of these compounds in various tissues (levels in μg/g of tissue shown in the parentheses) with the highest level observed in the kidney (50.5), followed by lung and spleen (15.4 each), serum (1.2), liver (0.9), and brain (0.2) after 30 min of administration . When BACs were administered orally (250 mg/kg), the levels of BAC reached their highest concentrations for the majority of the tissues after 24 h (2 h for liver) with the level in kidney (5.25) > lung (2.75) > liver (0.72) > blood (0.34) (not determined in brain). , Therefore, BACs are orally bioavailable and distribute broadly throughout tissues in vivo. However, the mechanisms of metabolism and disposition of BACs in humans have not been studied and this represents a barrier to our understanding of the systemic toxicology of BACs.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of Benzalkonium Chlorides by Human Hepatic Cytochromes P450

Seguin

Herron

Lopez

et al. 2019

Chem. Res. Toxicol.

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Benzalkonium chlorides (BACs) are widely used as disinfectants in cleaning products, medical products, and the food processing industry. Despite a wide range of reported toxicities, limited studies have been conducted on the metabolism of these compounds in animal models and none in human-derived cells or tissues. In this work, we report on the metabolism of BACs in human liver microsomes (HLM) and by recombinant human hepatic cytochrome P450 (CYP) enzymes. BAC metabolism in HLM was NADPH-dependent and displayed apparent half-lives that increased with BAC alkyl chain length (C 10 < C 12 < C 14 < C 16), suggesting enhanced metabolic stability of the more lipophilic, longer chain BACs. Metabolites of d 7-benzyl labeled BAC substrates retained all deuteriums and there was no evidence of N-dealkylation. MS/MS fragmentation of BAC metabolites confirmed oxidation occurs on the alkyl chain region. Major metabolites of C 10-BAC were identified as ω-hydroxy-, (ω−1)-hydroxy-, (ω, ω−1)-diol-, (ω−1)-ketone-, and ω-carboxylic acid-C 10-BAC by LC-MS comparison with synthetic standards. In a screen of hepatic CYP isoforms, recombinant CYP2D6, CYP4F2, and CYP4F12 consumed substantial quantities of BAC substrates and produced the major microsomal metabolites. The use of potent pan-CYP4 inhibitor HET0016, the specific CYP2D6 inhibitor quinidine, or both confirmed major contributions of CYP4-and CYP2D6-mediated metabolism in the microsomal disappearance of BACs. Kinetic characterization of C 10-BAC metabolite formation in HLM demonstrated robust Michaelis-Menten kinetic parameters for ω-hydroxylation (V max = 380 pmol/min/mg, K m = 0.69 μM) and (ω −1)-hydroxylation (V max = 126 pmol/min/mg, K m = 0.13 μM) reactions. This work illustrates important roles for CYP4-mediated ω-hydroxylation and CYP2D6/CYP4-mediated (ω−1)hydroxylation during the hepatic elimination of BACs, an environmental contaminant of emerging concern. Furthermore, we demonstrate that CYP-mediated oxidation of C 10-BAC mitigates the potent inhibition of cholesterol biosynthesis exhibited by this short-chain BAC.

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Comparative study on toxic effects induced by oral or intravascular administration of commonly used disinfectants and surfactants in rats

Yang

Zhang

Tang

et al. 2011

J of Applied Toxicology

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Accidental ingestion or injection of household products sometimes occurs due to their accessibility, but the toxic manifestations have not been well characterized when they are internally administered. The aim of this study was to investigate the toxic effects induced by ingestion or injection of different ionic surfactants and disinfectants in rats. The test drugs involved benzalkonium and benzethonium (BZK and BZT, both cationic surfactants used as disinfectants), alkyldiaminoethylglycine (AEG, an amphoteric surfactant used as a disinfectant), linear alkylbenzenesulfonate (LAS, an anionic surfactant), polyoxyethylene cetylether (PEC, a nonionic surfactant), chlorhexidine (CHX, not a surfactant but a disinfectant) and saline (control). Male Sprague-Dawley rats were administered one of the test drugs orally (p.o.), intravenously (i.v.) or intraarterially (i.a.). The fatal effects appeared rapidly (<30 min) in i.v.-administered rats, while taking hours (>5 h) in i.a./p.o.-administered rats after a dose of around LD(50) , although the progress and degree of toxic effects varied among the drugs tested. In intravascular administration, BZK and BZT were fatal at doses of 15-20 mg kg(-1) . Higher concentrations in lung and kidney than in blood were determined. CHX showed a high toxic effect compared with cationic surfactants. The rats administered anionic (LAS) or amphoteric (AEG) surfactant died in less than 24 h at doses over 100 mg kg(-1) . In p.o. administration, the toxic effects were concentration/dose-dependent, and all rats administered high doses of surfactants except for PEC died at 5-20 h. The overall toxic ranks could be: cationic surfactant/CHX> anionic/amphoteric surfactant > nonionic surfactant.

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Kinetic characteristics and toxic effects of benzalkonium chloride following intravascular and oral administration in rats

Cited by 18 publications

References 24 publications

Manufacturing Different Types of Solid Dispersions of BCS Class IV Polyphenol (Daidzein) by Spray Drying: Formulation and Bioavailability

Manufacturing Different Types of Solid Dispersions of BCS Class IV Polyphenol (Daidzein) by Spray Drying: Formulation and Bioavailability

Metabolism of Benzalkonium Chlorides by Human Hepatic Cytochromes P450

Comparative study on toxic effects induced by oral or intravascular administration of commonly used disinfectants and surfactants in rats

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