Pharmacokinetics and tolerance of repeated oral doses of loxiglumide
Setnikar, I.; Chisté, R.; Giacovelli, G.; Rovati, L.C.
Arzneimittel-Forschung 39(11): 1454-1459
1989
ISSN/ISBN: 0004-4172 PMID: 2619779 Document Number: 342272
The study was conducted on 6 adult healthy subjects (5 males and 1 female) in order to investigate the pharmacokinetics and tolerance of repeated b.i.d. oral administration for 7 days of tablets containing 400 mg/ of loxiglumide (CR 1505). The pharmacokinetic of loxiglumide in plasma after the first single dose of 400 mg is characterized by a lag time of 16 .+-. 4 min, a rapid invasion (kinv = 10 h-1), a Cmax of 11.9 .+-. 5.1 mg/l at tmax of 2.3 .+-. 0.8 h, a mean residence time (MRT) of 6.9 .+-. 1.1 h and an AUC of 60.6 .+-. 16.3 (mg/l) .times.h. After the last dose of 400 mg the lag time was 17 .+-. 6 min, the Cmax 12.7 .+-. 3.8 mg.l at tmax of 2.1 .+-. 0.8 h, a MRT of 11.0 .+-. 1.9 h and an AUC of 109.8 .+-. 39.9 (mg/l) .times. h. The increases of the AUC and of MRT were statistically significant and are probably due to an accumulation of loxiglumide which occurs during the repeated dose course and reaches the steady state within 48 h of repeated administration. Due to this accumulation the Cmax increased by 7%. The increase was not statistically significant or clinically relevant. No dose adjustment seems required during a repeated dose dosing schedule with 400 mg b.i.d. In the urine loxiglumide and 3 metabolites were found, which were called Metabolite (Met.) 11.2, Met. 12.0 and Met. 12.8. Met. 12.0 was the most abundant, accounting for 45% of the loxiglumide related substances excreted in the urine. It was followed by Met. 12.8 (29%), Met. 11.2 (17%) and loxiglumide (9%). The urinary excretion of loxiglumide and related substances accounts for 23% of the administered dose. About 80% of the excretion is completed within the 12 h following the administration. No severe adverse reactions were reported by the subjects or observed by the investigator. Two subjects complained loose stools on the 7th day of repeated doses and one subject complained mild and transient nausea on 3rd and 4th day of repeated doses administration. No clinically significant or drug related abnormality of laboratory values was found. No drop out related or unrelated to the drug occurred.