Pharmacokinetics of trimethylamine in rats, including the effects of a synthetic diet

Abstract

1. The pharmacokinetic profile of trimethylamine (TMA) was examined in the male Wistar rat and the effects of a synthetic diet on TMA pharmacokinetics were also evaluated. 2. The concentrations of TMA and its N-oxide in blood were analysed by a sensitive headspace gas chromatographic assay. 3. The pharmacokinetics of TMA were essentially linear for intravenous (i.v.) bolus doses of 10-40 mg kg(-1). Over the range of administered i.v. doses, the concentrations of TMA in blood declined approximately monoexponentially with half-lives of 2.03-2.48 h. The Vd of TMA ranged from 3.2 to 4.39 l kg(-1) and clearance ranged from 18.78 to 23.92 ml min(-1) kg(-1). The peak concentration of TMA in blood occurred at 1 h after oral administration of a 20 mg kg(-1) dose and the bioavailability for the oral dose averaged 81%. 4. Peak concentrations of trimethylamine N-oxide (TMAO) in blood were attained at 0.73 and 1 h after i.v and oral administration of TMA (20 mg kg(-1)), respectively. 5. Feeding the male Wistar rat with a synthetic diet resulted in a twofold decrease in the clearance of TMA. Furthermore, the concentration of TMAO in blood after i.v. administration of TMA peaked at 1.25 h in rat placed on the synthetic diet as opposed to 0.75 h in rat placed on normal laboratory rat chow. The altered pharmacokinetic profile of TMA and its N-oxide suggest a diminished drug-elimination capacity in rat placed on the synthetic diet. 6. Dietary modulation of flavin-containing monooxygenase (FMO) activity may explain the effects of diet on the pharmacokinetics of TMA and its N-oxide.

Trimethylamine: Metabolic, Pharmacokinetic and Safety Aspects

“…There is very little information in the literature regarding the distribution of TMA in humans, although work by Nnane and Damani [73] and Smith et al [74] indicate that this compound undergoes extensive distribution into rat tissues with an apparent volume of distribution of 3.2 to 4.39 L/kg following intravenous bolus dose administration (10-40 mg/kg) [73]. Also, after intravenous bolus administration (10-40 mg/kg), the concentration of TMA in blood declined in a monoexponential manner, suggesting spontaneous distribution [73].…”

“…In 2001, Nnane and Damani studied the pharmacokinetics of TMA and TMNO in rats [73], although, predicting similar results in humans may be difficult given the diffe- Trimethylamine-N-oxide (abundant in fish) can also be converted by enterobacteria to form trimethylamine. Following absorption from the gastrointestinal tract, trimethylamine is metabolized by flavin-containing monooxygenase enzyme (isoform 3) to form trimethylamine-Noxide with subsequent urinary excretion of trimethylamine-N-oxide and, to a lesser extent unchanged trimethylamine.…”

“…rences in expression of FMO enzymes [77][78][79] and gastrointestinal physiology [52,64] between rats and humans. The oral bioavailability of a 20 mg/kg oral dose of TMA in the male Wistar rat was approximately 81 % [73] with peak concentrations occurring in blood at 1 hour [73].…”

“…Whilst the pharmacokinetics of TMA and TMNO has not been fully elucidated in humans, there are a range of studies in humans and animals that provide information on the fate of these compounds in the body [15,[73][74][75] (Fig. 1).…”

Detection of food intake in a marine mammal using marine osmolytes and their analogues as dietary biomarkers

“…n/r: not recorded; n/m: not measured ca. 1 h and decreased monoexponentially with an approximate half-life of 2 to 3 h (Smith et al 1994, Nnane & Damani 2001. In studies with radioactively labelled TMAO, 95% of an oral dose was excreted from the body within 24 h in rats (Mitchell et al 1997) and humans (Al-Waiz et al 1987b).…”