Pharmacokinetics and safety of calcium L-threonate in healthy volunteers after single and multiple oral administrations.
To evaluate the pharmacokinetics of L-threonate after single or multiple oral administrations and its safety profile in healthy Chinese volunteers. This was an open-label, single- and multiple-dose study. The subjects were assigned to receive a single dose, 675, 2025, or 4050 mg, of calcium L-threonate (n=12) or repeated doses of 2025 mg twice daily for 4 d (n=12). Serial plasma and urine samples were analyzed with HPLC-MS/MS. Pharmacokinetic parameters of L-threonate were calculated using non-compartmental analysis with WinNonlin software.
In the single dose group, C(max) reached at 2.0 h and the mean t(1/2) was approximately 2.5 h. Area under curve (AUC) and C(max) increased with dose escalation, but dose proportionality was not observed over the range of 675 to 4050 mg. AUC and C(max) in the fasted subjects were lower compared with those in the non-fasted subjects. Cumulative urinary excretion of L-threonate over 24 h represented 5.9% of the administered dose with a mean Cl/r of 0.8 L/h. In the multiple-dose study, no accumulation appeared upon repeated doses of 2025 mg twice daily for 4 d. There were no serious adverse events that occurred during this study.
Calcium L-threonate was well tolerated in healthy Chinese subjects, with no pattern of dose-related adverse events. Plasma exposure increased with dose escalation, but linear pharmacokinetics were not observed over the studied doses. L-threonate was absorbed rapidly, and its absorption was enhanced by food intake. No systemic accumulation appeared after repeated administrations.
The introduction is the most interesting part of the article.
L-Threonic acid is an active metabolite of vitamin C5, 6, 7, 8. It has been reported that L-threonic acid exhibits significant stimulatory action on vitamin C uptake and prolongs the retention of vitamin C in human T-lymphoma cells9, 10. It is also well known that vitamin C is a marker for osteoblast formation and has been shown to stimulate procollagen and enhance collagen synthesis11, 12, 13, 14. Therefore, L-threonic acid may play a role in the mineralization process through its positive action on vitamin C. This hypothesis was confirmed in 1999 by Rowe DJ15. It was reported that in vitro treatment with ascorbate-containing vitamin C metabolites enhanced the formation of the mineralized nodules and collagenous proteins and that L-threonate was one of the metabolites that was found to influence the mineralization process15. Recently, a preclinical study was performed to investigate the effect of L-threonate on bone resorption of rabbit osteoclasts16. This study contained a total of six culture groups, including one control group and five groups treated with drugs (calcium L-threonate, sodium L-threonate, alendronate, 17β-estradiol and calcium gluconate). The levels of type I collagen C-telopeptide (CTx) and bone slice resorptive area were measured. This study found that L-threonate, especially calcium L-threonate, inhibited the bone resorption of osteoclasts in vitro; however, the reductive effects on the CTx level and resorptive area were not as significant as alendronate and 17β-estradiol at the same concentration.
Calcium L-threonate ((2R,3S)-2,3,4-trihydroxy butyric acid calcium) (Figure 1) is a novel drug developed for the treatment of osteoporosis and as a calcium supplement. Phase I clinical trials of calcium L-threonate, including tolerance, pharmacokinetics and calcium absorption evaluation, were performed in Peking Union Medical College Hospital. In this paper, the pharmacokinetics of L-threonate after single or multiple oral administrations and its safety profile in healthy Chinese volunteers are presented.