Dose dependency in the oral bioavailability of an organic cation model, tributylmethyl ammonium (TBuMA), in rats: Association with the saturation of efflux by the P-gp system on the apical membrane of the intestinal epithelium

Kim, Moon Kyoung; Lv, Han; Choi, Min Koo; Han, Yong‐Hae; Kim, Dae‐Duk; Chung, Suk‐Jae; Shim, Chang‐Koo

doi:10.1002/jps.20456

Cited by 11 publications

(6 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…OCTs promote both the intestinal uptake of such cations into the systemic circulation and facilitate their secretion in the nephron (Zhang et al, 1998;Slitt et al, 2001). The prototypical organic cations tetraethylammonium and tributylmeth- dmd.aspetjournals.org ylammonium are actively transported across the intestinal mucosa by a sodium-independent cation transporter (OCT) system (Bowman and Hook, 1972;Koepsell, 1998;Kim et al, 2005). As Bmim-Cl has structural characteristics similar to these water-soluble compounds, it is likely that its uptake from the intestine into the systemic circulation is mediated by these transporters present in the intestinal mucosa.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Dose and Route on the Toxicokinetics and Disposition of 1-Butyl-3-methylimidazolium Chloride in Male F-344 Rats and Female B6C3F1 Mice

Sipes¹,

Knudsen²,

Kuester³

2007

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:These studies characterize the effect of dose and route of administration on the disposition and elimination of the ionic liquid, 1-butyl-3-methylimidazolium chloride (Bmim-Cl). After i.v. (5 mg/ kg) or oral (50 mg/kg) administration to male F-344 rats [14 C]BmimCl detected in blood decreased rapidly. Clearance rates from the blood after i.v. and oral administration were similar (7.4 and 11.9 ml/min, respectively). Systemic bioavailability was determined to be 62.1% of a 50 mg/kg dose in rats. Urinary excretion of the parent compound by rats was the major route of elimination (i.v.: 91% in 24 h; oral: 55-74% in 24 h). The rates and routes of elimination were not affected by escalation of dose (0.5-50 mg/kg) or repeated oral administration (five daily administrations, 50 mg/kg) and were similar in male rats and B6C3F1 female mice (86-95% of dose eliminated in 24 h). Apparent systemic exposure to Bmim-Cl after dermal administration was dependent upon vehicle, as assessed by the percentage of dose eliminated in urine after application in a particular vehicle (water: 1%; ethanol/water: 3%; and dimethylformamide/water: 13% of dose). Regardless of gender, species, dose, route, or number of exposures, high-pressure liquid chromatography-UV/visible-radiometric analyses of urine samples showed a single peak that coeluted with the Bmim-Cl standard. These studies illustrate that systemic bioavailability of Bmim-Cl is high, tissue disposition and metabolism are negligible, and absorbed compound is extensively extracted by the kidney and eliminated in the urine as the parent compound.

show abstract

Section: Discussionmentioning

confidence: 99%

The Effects of Dose and Route on the Toxicokinetics and Disposition of 1-Butyl-3-methylimidazolium Chloride in Male F-344 Rats and Female B6C3F1 Mice

Sipes¹,

Knudsen²,

Kuester³

2007

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…In rats, Kim et al observed that oral bioavailability of a model QAC compound (tributylmethyl ammonium) increased with dose from 17% up to 35%. The dose-dependent bioavailability is attributed to saturation of intestinal P-glycoprotein (P-gp) efflux at higher doses. , Furthermore, P-gp gene knockout mice displayed enhanced persistence of intravenously (IV)-dosed QACs . In rats dosed orally with cetyltrimethylammonium (ATMAC C16) or BACs (C12 and C14), , time courses show intestinal absorption occurs over several hours, with these QACs persisting beyond 24 h in blood and tissues.…”

Section: Human Exposurementioning

confidence: 99%

Quaternary Ammonium Compounds: A Chemical Class of Emerging Concern

Arnold,

Blum,

Branyan

et al. 2023

Environ. Sci. Technol.

View full text Add to dashboard Cite

Quaternary ammonium compounds (QACs), a large class of chemicals that includes high production volume substances, have been used for decades as antimicrobials, preservatives, and antistatic agents and for other functions in cleaning, disinfecting, personal care products, and durable consumer goods. QAC use has accelerated in response to the COVID-19 pandemic and the banning of 19 antimicrobials from several personal care products by the US Food and Drug Administration in 2016. Studies conducted before and after the onset of the pandemic indicate increased human exposure to QACs. Environmental releases of these chemicals have also increased. Emerging information on adverse environmental and human health impacts of QACs is motivating a reconsideration of the risks and benefits across the life cycle of their production, use, and disposal. This work presents a critical review of the literature and scientific perspective developed by a multidisciplinary, multi-institutional team of authors from academia, governmental, and nonprofit organizations. The review evaluates currently available information on the ecological and human health profile of QACs and identifies multiple areas of potential concern. Adverse ecological effects include acute and chronic toxicity to susceptible aquatic organisms, with concentrations of some QACs approaching levels of concern. Suspected or known adverse health outcomes include dermal and respiratory effects, developmental and reproductive toxicity, disruption of metabolic function such as lipid homeostasis, and impairment of mitochondrial function. QACs' role in antimicrobial resistance has also been demonstrated. In the US regulatory system, how a QAC is managed depends on how it is used, for example in pesticides or personal care products. This can result in the same QACs receiving different degrees of scrutiny depending on the use and the agency regulating it. Further, the US Environmental Protection Agency's current method of grouping QACs based on structure, first proposed in 1988, is insufficient to address the wide range of QAC chemistries, potential toxicities, and exposure scenarios. Consequently, exposures to common mixtures of QACs and from multiple sources remain largely unassessed. Some restrictions on the use of QACs have been implemented in the US and elsewhere, primarily focused on personal care products. Assessing the risks posed by QACs is hampered by their vast structural diversity and a lack of quantitative data on exposure and toxicity for the majority of these compounds. This review identifies important data gaps and provides research and policy recommendations for preserving the utility of QAC chemistries while also seeking to limit adverse environmental and human health effects.

show abstract

“…The transport mechanisms involved in absorption of quaternary ammonium compounds by enterocytes and the transfer in a submucosal direction are unknown; luminal uptake seems to be mediated by a sodium‐dependent carrier . It must be considered that net absorption is most likely influenced by intestinal efflux via P‐glycoprotein, as shown for other quaternary compounds . P‐glycoprotein is increasingly abundant along the small intestine but less expressed in the colon .…”

Section: Discussionmentioning

confidence: 99%

Extended‐release but not immediate‐release and subcutaneous methylnaltrexone antagonizes the loperamide‐induced delay of whole‐gut transit time in healthy subjects

Kolbow

Modeß

Wegner

et al. 2015

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Methylnaltrexone (MNTX) is approved for subcutaneous treatment (MNTX-SC) of opioid induced constipation. MNTX in oral immediate-release (MNTX-IR) and extended-release (MNTX-ER) dosage forms may antagonize the opioid induced delay in oro-cecal transit time (OCT) as measured by using radiolabeled lactulose. Because lactulose acts laxative by its own and efficacy of MNTX on colon transit time (CTT) was unknown, the opioid antagonistic effects MNTX-IR and MNTX-ER (both 500 mg) relative to MNTX-SC (12 mg) were evaluated in 15 healthy subjects with loperamide (LOP, 3 × 4 mg, 12 hourly) induced experimental constipation using the sulfasalazine/sulfapyridine method and radio-opaque markers to measure OCT and whole gut transit time (WGT). MNTX-ER significantly antagonized the LOP effects in 12 of our 15 subjects who responded to LOP with prolongation of WGT by 20.6-74.1 h (OCT by 0.50-10.5 h, CTT by 18.3-73.6 h). MNTX-SC and MNTX-IR were without significant influence. Compared to MNTX-SC, bioavailability of MNTX-IR and MNTX-ER was 1.53-5.49% and 0.11-1.24%, respectively. MNTX-SC and MNTX-IR achieved active serum levels only for ∼ 3-5 h. MNTX-ER antagonized the opioid-induced delay of CTT most likely by local effects on µ-opioid receptors in the colon.

show abstract

Dose dependency in the oral bioavailability of an organic cation model, tributylmethyl ammonium (TBuMA), in rats: Association with the saturation of efflux by the P-gp system on the apical membrane of the intestinal epithelium

Cited by 11 publications

References 33 publications

The Effects of Dose and Route on the Toxicokinetics and Disposition of 1-Butyl-3-methylimidazolium Chloride in Male F-344 Rats and Female B6C3F1 Mice

The Effects of Dose and Route on the Toxicokinetics and Disposition of 1-Butyl-3-methylimidazolium Chloride in Male F-344 Rats and Female B6C3F1 Mice

Quaternary Ammonium Compounds: A Chemical Class of Emerging Concern

Extended‐release but not immediate‐release and subcutaneous methylnaltrexone antagonizes the loperamide‐induced delay of whole‐gut transit time in healthy subjects

Contact Info

Product

Resources

About