Pharmacokinetics of trimethylamine in rats, including the effects of a synthetic diet.
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.
Nnane
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Temple University School of Pharmacy, Philadelphia, PA 19140, USA. innane@unix.temple.edu
Damani
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D000818:Animals; D019540:Area Under Curve; D002138:Calibration; D002849:Chromatography, Gas; D005526:Food, Formulated; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008744:Methylamines / Q000493:pharmacokinetics*; D008995:Monoamine Oxidase / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D008744:Methylamines; D008995:Monoamine Oxidase; C023336:trimethylamine