Oral Bioavailability of Deuterated L‐carnitine in Healthy Volunteers

Abstract

BACKGROUND Deuterium, the stable isotope of hydrogen was discovered in 1931. Since then the use of deuterated molecules have allowed several advancements in the field of chemical biology. For example: in elucidating mechanisms of reactions, tracking metabolic products, and more recently, the enhancement of pharmacokinetic parameters in already existing drugs. L-carnitine is an amino acid derivative, quaternary ammonium molecule with hygroscopic properties that displays an essential role in the fatty acid metabolism in mammals. L-carnitine is an example of a molecule that is both endogenously synthetized and exogenously administered in the forms of dietary products, supplements, and medicine. This poses a challenge differentiating the source of L-carnitine measured in plasma. OBJECTIVES Our study, aims to use deuterated molecules in pharmacokinetics, for distinguishing endogenous synthesized molecules from exogenously administered ones, like L-carnitine. We have developed a method based on deuteration and posterior detection of L- carnitine using high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). METHODS The study was conducted over an open, four period with a 1-week washout interval and six healthy subjects were recruited. Capsules containing 500 mg of L-carnitine which contained different doses of deuterated (D3) L-carnitine (10,30,100 and 100mg of D3 L-carnitine and 490,470 and 400mg of L-carnitine) in each period were administered to each participant. Plasma L-carnitine D3 concentrations were analysed by liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) with multiple reactions monitoring (MRM). The method linearity ranged from 10 to 1000 ng/mL. RESULTS The following pharmacokinetic parameters were obtained from the L-carnitine D3 plasma concentration vs. time curves: AUClast (72.16, 613.48, 2450.29ng*h/mL [mean]), Cmax (19.25, 75.59, 216.79 ng/mL[mean]) and Tmax (3.5, 3.5, 3.5 h [median]) for 10 mg, 30 mg and 100 mg, respectively. The coefficient of variation for rate and extent of absorption were 55.37% and 65.10% (ratio 3/4 period; 100 mg), respectively. Linearity between the pharmacokinetic parameters was demonstrated by Pearson Correlation. The plasma concentrations showed correlation with dose (10, 30 and 100 mg). CONCLUSION This shows that deuterated L-carnitine displays a high variability coefficient and demonstrates linearity among doses of 10, 30 and 100 mg. These results are consistent with previous literature. The method presented here adds to the existing consensus that deuteration is valuable in studying the pharmacokinetics of endogenously synthesized substances.