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 V d of TMA ranged from 3.2 to 4.39 l kg -1 and clearance ranged from 18.78 to 23.92ml 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 0.75 and 1 h after i.v and oral administration of TMA (20mg 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.