Age associated decline in the conversion of leucine to ß-Hydroxy-ß-Methylbutyrate in rats.

BACKGROUND: The loss of muscle mass is considered to be a major factor contributing to strength decline during aging. ß-Hydroxy-ß-Methylbutyrate (HMB), a metabolite of leucine has been shown to enhance muscle protein synthesis and attenuate loss of muscle mass by multiple pathways. However, the production and regulation of endogenous levels of HMB over the lifespan have not been investigated. OBJECTIVE: The objective of the present study was to do a cross-sectional analysis of the basal plasma levels of HMB in male Sprague-Dawley rats of different ages and to compare the efficiency of conversion of leucine to HMB in young versus older rats. METHODS: Plasma levels of HMB and α-ketoisocaproate (KIC) were analyzed in rats of different age groups (3, 9, 12 and 24months old, n=10 per group). Levels of 4-HPPD, the enzyme involved in the conversion of KIC to HMB in the liver were determined by ELISA. The conversion efficiency of leucine to HMB was compared between 3 and 24month rats after an oral bolus dose of leucine. RESULTS: Endogenous circulating levels of HMB were significantly reduced in older age rats compared to young rats (100±3.7 vs 156±10 (mean±SEM), ng/mL, p<0.001). A significant negative correlation was seen between HMB levels and age. The liver levels of 4-HPPD were found to be significantly lower in old versus young rats. Consistent with this, the conversion efficiency of leucine to HMB was significantly lower in the aged versus young cohorts. CONCLUSIONS: In summary, this study depicts for the first time that the basal levels of HMB, a metabolite of amino acid leucine, declines with age, and that this decline is due to perturbations in the key enzyme 4-HPPD which catalyzes the conversion of KIC to HMB. As a consequence, the efficiency of conversion of leucine to HMB is diminished in older rats compared to younger rats.

The relative bioavailability of the calcium salt of ß-hydroxy-ß-methylbutyrate is greater than that of the free fatty acid form in rats.

BACKGROUND: ß-Hydroxy-ß-methylbutyrate (HMB) supplementation has been demonstrated to enhance muscle protein synthesis and attenuate loss of muscle mass by multiple pathways. The beneficial effects of HMB have been studied by using either the calcium salt, monohydrate, of HMB (CaHMB) or the free acid form (FAHMB). OBJECTIVE: The present study was designed to compare the pharmacokinetics and relative bioavailability of the 2 forms of HMB administered as a liquid suspension in male Sprague-Dawley rats. METHODS: CaHMB at 30, 100, and 300 mg/kg and equivalent doses of FAHMB at 24.2, 80.8, and 242 mg/kg were administered orally as a liquid suspension to male Sprague-Dawley rats. A single i.v. dose of 5 mg/kg CaHMB, corresponding to an equivalent dose of 4.04 mg/kg FAHMB, was also administered. Plasma concentrations of HMB were analyzed by liquid chromatography tandem mass spectrometry, and pharmacokinetic variables and relative bioavailability of the 2 forms of HMB were determined. RESULTS: After oral administration, the area under the plasma concentration time curve (AUC) from time 0 to time t (0-t) and from time 0 to infinity (0-∞) and the maximum (peak) plasma concentration (Cmax) for CaHMB were significantly greater than for FAHMB, whereas the time to reach Cmax did not differ from that of FAHMB. The relative bioavailability of CaHMB was 49%, 54%, and 27% greater than that of FAHMB for the 3 respective oral doses tested. After i.v. administration, the AUCs 0-t and 0-∞ of the calcium salt were significantly greater than those of FAHMB. The relative bioavailability of CaHMB was 80% greater than that of FAHMB. The higher relative bioavailability of CaHMB may be attributable to its low systemic clearance compared with FAHMB. CONCLUSIONS: This study demonstrates the enhanced relative bioavailability of CaHMB compared with FAHMB. Further studies are warranted to understand the physiologic mechanisms contributing to the differences in systemic clearance.

Enhanced bioavailability and bioefficacy of an amorphous solid dispersion of curcumin.

Curcumin has been shown to have a wide variety of biological activities for various human diseases including inflammation, diabetes and cancer. However, the poor oral bioavailability of curcumin poses a significant pharmacological barrier to its use therapeutically and/or as a functional food. Here we report the evaluation of the bioavailability and bio-efficacy of curcumin as an amorphous solid dispersion (ASD) in a matrix consisting of hydroxypropyl methyl cellulose (HPMC), lecithin and isomalt using hot melt extrusion for application in food products. Oral pharmacokinetic studies in rats showed that ASD curcumin was ∼13-fold more bioavailable compared to unformulated curcumin. Evaluation of the anti-inflammatory activity of ASD curcumin in vivo demonstrated enhanced bio-efficacy compared to unformulated curcumin at 10-fold lower dose. Thus ASD curcumin provides a more potent and efficacious formulation of curcumin which may also help in masking the colour, taste and smell which currently limit its application as a functional food ingredient.