Pre-formulation studies of resveratrol.

CONTEXT: Resveratrol, a natural compound found in grapes, has potential chemotherapy effects but very low oral bioavailability in humans. OBJECTIVE: To evaluate the solubility, pH stability profile, plasma protein binding (PPB) and stability in plasma for resveratrol. METHODS: Solubility of resveratrol was measured in 10 common solvents at 25 °C using HPLC. The solution state pH stability of resveratrol was assessed in various United States Pharmacopeia buffers ranging from pH 2 to 10 for 24 h at 37 °C. Samples were analyzed up to 24 h. Human PPB was determined using ultracentrifugation technique. Standard solutions of drug were spiked to blank human plasma to yield final concentrations of 5, 12.5 or 25 µg/mL for determination. Finally, stability of resveratrol in human and rat plasma was also assessed at 37 °C. Aliquots of blank plasma were spiked with a standard drug concentration to yield final plasma concentration of 50 µg/mL. Samples were analyzed for resveratrol concentration up to 96 h. RESULTS: Resveratrol has wide solubility ranging from 0.05 mg/mL in water to 374 mg/mL in polyethylene glycol 400 (PEG-400). Resveratrol is relatively stable above pH 6 and has maximum degradation at pH 9. The mean PPB of resveratrol is 98.3%. Resveratrol degrades in human and rat plasma in a first-order process with mean half lives of 54 and 25 h, respectively. CONCLUSION: Resveratrol is more soluble in alcohol and PEG-400 and stable in acidic pH. It binds highly to plasma proteins and degrades slower in human then rat plasma.

Biotransformation and pharmacokinetics of inositol hexanicotinate in rats.

Inositol hexanicotinate (IHN) is an ester of the anti-hyperlipidemic drug nicotinic acid (NA). This study assessed the hydrolysis rate of IHN in human and rat plasma, and pharmacokinetics of the drug using a rat animal model. IHN (10 or 50 µg/mL) was incubated in plasma at 37 °C for 72 h. Kinetic parameters were determined based on the disappearance of IHN and the appearance of NA. The mean IHN disappearance and NA appearance half-lives were 1.07 and 3.93 h in human plasma, and 0.152 and 2.68 h in rat plasma. Increasing the initial plasma concentration to 50 µg/mL increased the NA appearance half-life in human and rat plasma to 4.66 and 6.47 h, respectively. After single 50 or 100 mg/kg intravenous dose of IHN to Sprague-Dawley rats, the drug showed statistically significant dose-dependent alterations in systemic clearance, suggesting a non-linear saturable elimination of IHN. Dose-normalized mean plasma levels of NA increased by 30% with increasing IHN dose (p < 0.02). The mean metabolic ratio (i.e. NA/IHN AUC ratio) significantly increased with increasing IHN dose (p < 0.05). The results provide first indication of saturable elimination and rapid disappearance of IHN, while niacin was slowly formed.