Sulpiride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Data source

Reference

Reference Type:

review article or handbook

Title:

Pharmacotoxicological aspects of levosulpiride.

Author:

Rossi F

Year:

1995

Bibliographic source:

Pharmacol Res. 1995 Feb;31(2):81-94.

Results and discussion

Any other information on results incl. tables

In rats treated with sulpiride 200 mg/kg by oral route the pharmacokinetic parameters were the following: Cmax 6.8µg/ml; tmax 3 h; t1/2 1.4 h; bioavailability 15%. The low bioavailability of sulpiride following oral administration (about 15%) is due not to the metabolism in the liver, but to a reduced absorption by the gastrointestinal tract. Many metabolites were obtained from rats and dogs orally treated with sulpiride. Particularly, in rats, metabolites represented 56% of the administered drug (60 mg/kg) and 38% of them were conjugates. In the dog, the metabolites represented 15% of the administered sulpiride (50 mg/kg), of which 4% were conjugates. However, none of the metabolites documented in these species was found in human urine. In the Rhesus monkeys treated with sulpiride at 10 mg/kg by oral or intravenous route, in both the urine and the bile were documented the following fractions of the administered dose: 60-80% sulpiride, 10-30% 5-oxopyrrolidine sulpiride and 3-8% unidentified metabolite. After intramuscular administration (50 mg) to healthy volunteers, the bioavailability of L-sulpiride is practically complete (about 99%), whereas the oral bioavailability of the same dosage is about 30%. The half-lives are 6.2, 8.3 and 9.7 h respectively, for the intravenous, intramuscular and oral administration (50 mg), with a total clearance of about 260 ml/min. Sulpiride is not bound to plasma proteins to any large extent. In dog plasma 16% of the sulpiride is bound over a concentration range of 1 to 50µg/ml. In human plasma 14% is bound over the same concentration range. Thus, the protein binding is constant and independent of sulpiride concentrations in dog plasma and human plasma. The results of a comparative pharmacokinetic study after single oral administration of D-, L- and racemic sulpiride demonstrated that the pharmacokinetic profiles are largely identical. Also, the urinary excretion is similar for racemic and L-sulpiride and accounts for about 65-70% of the dose after intravenous administration, totally as unchanged drug. The mean renal clearance is in the range 260-310 ml/min after intravenous administration of the two drugs (L- and racemic-sulpiride) and suggests a tubular secretion of sulpiride since clearance exceeded glomerular filtration rate. This conclusion is also supported by data on metabolism of sulpiride.

Applicant's summary and conclusion

Executive summary:

In rats treated with sulpiride 200 mg/kg by oral route the pharmacokinetic parameters were the following: Cmax 6.8 µg/ml; tmax 3 h; t1/2 1.4 h; bioavailability 15%. The low bioavailability of sulpiride following oral administration (about 15%) is due not to the metabolism in the liver, but to a reduced absorption by the gastrointestinal tract. Many metabolites were obtained from rats and dogs orally treated with sulpiride. Particularly, in rats, metabolites represented 56% of the administered drug (60 mg/kg) and 38% of them were conjugates. In the dog, the metabolites represented 15% of the administered sulpiride (50 mg/kg), of which 4% were conjugates. However, none of the metabolites documented in these species was found in human urine. In the Rhesus monkeys treated with sulpiride at 10 mg/kg by oral or intravenous route, in both the urine and the bile were documented the following fractions of the administered dose: 60-80% sulpiride, 10-30% 5-oxopyrrolidine sulpiride and 3-8% unidentified metabolite. After intramuscular administration (50 mg) to healthy volunteers, the bioavailability of L-sulpiride is practically complete (about 99%), whereas the oral bioavailability of the same dosage is about 30%. The half-lives are 6.2, 8.3 and 9.7 h respectively, for the intravenous, intramuscular and oral administration (50 mg), with a total clearance of about 260 ml/min. Sulpiride is not bound to plasma proteins to any large extent. In dog plasma 16% of the sulpiride is bound over a concentration range of 1 to 50 µg/ml. In human plasma 14% is bound over the same concentration range. Thus, the protein binding is constant and independent of sulpiride concentrations in dog plasma and human plasma. The results of a comparative pharmacokinetic study after single oral administration of D-, L- and racemic sulpiride demonstrated that the pharmacokinetic profiles are largely identical. Also, the urinary excretion is similar for racemic and L-sulpiride and accounts for about 65-70% of the dose after intravenous administration, totally as unchanged drug. The mean renal clearance is in the range 260-310 ml/min after intravenous administration of the two drugs (L- and racemic-sulpiride) and suggests a tubular secretion of sulpiride since clearance exceeded glomerular filtration rate. This conclusion is also supported by data on metabolism of sulpiride.