Metabolism of sulpiride: Determination of the chemical structure of its metabolites in rat, dog and man

Abstract

Results concerning the metabolism and pharmacokinetics of Sulpiride in rats have been previously reported. The present study describes the separation, quantification and determination of the chemical structure of the sulpiride metabolites found in the urine and plasma of rats, dogs and humans. The metabolites were separated by means of multicolumn HPLC and their structure then determined by mass spectrometry, IR and UV spectroscopy. Furthermore, the chemical structure of the six isolated metabolites as well as unchanged product obtained by biological pathways was confirmed by comparison with that of the synthesized reference products.The metabolites obtained from rat and dog were : 5-aminosulfonyl-N-[(1-ethyl-2-pyrrolidinYl)methyl]-2-hydroxybenzamide (in rat only), 5-aminosulfonyl-N-[(2-pyrrolidinyl)methyl]-2]-2-methoxybenzamide.In the rat, metabolites represented 56 % of the administered drug of which 38 % were conjugates; in the dog, they represented 15 % of which 4 % were conjugates. None of these metabolites was found in human urine; the pharmacological properties of sulpiride could therefore be attributed to the unchanged product.

Pharmacokinetic Evaluations of Sulpiride After Intravenous, Intramuscular, and Oral Single-Dose Administration in Jennies (Equus asinus)

“…However, the unmetabolized drug was found to be predominant in all the tested species (with about 90% of an IV dose recovered unchanged in the urine [17]), indicating not only that a limited role in reducing the systemic availability of SLP can be attributed to the liver but also and of greater importance that the pharmacologic properties of SLP can be essentially attributed to the unchanged agent [27]. If a similar metabolic pattern is assumed for donkeys, it might be hypothesized that SLP will not accumulate substantially when given at 1 mg/kg/d for several days of therapy.…”

“…If a similar metabolic pattern is assumed for donkeys, it might be hypothesized that SLP will not accumulate substantially when given at 1 mg/kg/d for several days of therapy. Indeed, the plasma concentration after 10 hours is very close to the LOQ, and SLP is known to not affect (inhibit) the metabolism [27]. A recent study has successfully proposed an in situ forming gel-like depot of a polyaspartamide-polylactide copolymer for once a week administration of SLP in rabbits [28].…”

“…An earlier metabolic study reported four different metabolic reactions of SLP in the liver; these vary in importance for different animal species [27]. However, the unmetabolized drug was found to be predominant in all the tested species (with about 90% of an IV dose recovered unchanged in the urine [17]), indicating not only that a limited role in reducing the systemic availability of SLP can be attributed to the liver but also and of greater importance that the pharmacologic properties of SLP can be essentially attributed to the unchanged agent [27].…”

Pharmacokinetics of Sulpiride After Intravenous Administration in Patients with Impaired Renal Function

“…Studies published to date have failed to reveal evidence of sulpiride metabolites in human urine or faeces (Imondi et al 1978;Sugnaux et al 1978). In healthy subjects, the plasma concentration of unchanged drug versus time and urinary excretion rate versus time, following intravenous administration, were consistent with a 2-compartment open model.…”

Absorption, metabolism and excretion of14C-sultopride in the rat

“…For this purpose we only use our own findings on suipiride metabolism (6,3). Albeit the data of Sugnaux and Benakis (17) on sulpiride metabolism are very similar to our own, it seems preferable to compare numbers which were found by similar methods and by using animals from the same breeder.…”