CONTEXT: Radiolabeling and dose fixation study of alpha-ketoglutarate (A-KG). OBJECTIVE: A-KG is a potential oral antidote for cyanide poisoning. Its protective efficacy in animals was best exhibited at a dose of 2.0 g/kg body weight, which when extrapolated to human is very high. The objective of this study was to reduce the dose of A-KG in humans with concomitant increase in its bioavailability, employing pharmacoscintigraphic techniques to assess kinetics in man. MATERIALS AND METHODS: A-KG was radiolabeled with technetium-99m pertechnetate (Tc-99m) and its purity, labeling efficiency, and stability in vitro were determined by instant thin layer chromatography. Time-dependent bio-absorption of the drug in rats and rabbits was assessed by gamma scintigraphy after oral administration of a tracer dose of (99m)Tc-A-KG mixed with nonradioactive A-KG at a concentration of 0.1-2.0 g/kg in the presence or absence of aqueous dilution. Furthermore, scintigraphy and radiometry studies were performed in healthy human volunteers using 5-20 g of A-KG, given in single or split doses followed by different quantity of water. Drug bioavailability was estimated periodically. RESULTS: High radiolabeling (>97%) of A-KG with a stability of 24 h in vitro was obtained. Less than 1% absorption of the drug occurred within 20 min after A-KG was administered in animals at a concentration of 2.0 g/kg body weight. One-tenth reduction in dose increased the bioavailability to 15%. Significant improvement in gastric emptying of the drug was achieved when the drug was administered along with 1-5 mL of water. In humans, two doses of 10 g A-KG given at an interval of 10 min, followed by 300 mL of water, increased the drug bioavailability to 40% as compared to a single dose of 20 g. DISCUSSION: Significant reduction in A-KG dose was achieved in humans as compared to the recommended dose in animals. CONCLUSION: Aqueous dilution improves the bioavailability of A-KG in humans.
CONTEXT: Radiolabeling and dose fixation study of alpha-ketoglutarate (A-KG). OBJECTIVE: A-KG is a potential oral antidote for cyanidepoisoning. Its protective efficacy in animals was best exhibited at a dose of 2.0 g/kg body weight, which when extrapolated to human is very high. The objective of this study was to reduce the dose of A-KG in humans with concomitant increase in its bioavailability, employing pharmacoscintigraphic techniques to assess kinetics in man. MATERIALS AND METHODS: A-KG was radiolabeled with technetium-99m pertechnetate (Tc-99m) and its purity, labeling efficiency, and stability in vitro were determined by instant thin layer chromatography. Time-dependent bio-absorption of the drug in rats and rabbits was assessed by gamma scintigraphy after oral administration of a tracer dose of (99m)Tc-A-KG mixed with nonradioactive A-KG at a concentration of 0.1-2.0 g/kg in the presence or absence of aqueous dilution. Furthermore, scintigraphy and radiometry studies were performed in healthy human volunteers using 5-20 g of A-KG, given in single or split doses followed by different quantity of water. Drug bioavailability was estimated periodically. RESULTS: High radiolabeling (>97%) of A-KG with a stability of 24 h in vitro was obtained. Less than 1% absorption of the drug occurred within 20 min after A-KG was administered in animals at a concentration of 2.0 g/kg body weight. One-tenth reduction in dose increased the bioavailability to 15%. Significant improvement in gastric emptying of the drug was achieved when the drug was administered along with 1-5 mL of water. In humans, two doses of 10 g A-KG given at an interval of 10 min, followed by 300 mL of water, increased the drug bioavailability to 40% as compared to a single dose of 20 g. DISCUSSION: Significant reduction in A-KG dose was achieved in humans as compared to the recommended dose in animals. CONCLUSION: Aqueous dilution improves the bioavailability of A-KG in humans.