Dose-dependent pharmacokinetics of sulpirideand sulpiride-induced prolactin secretionin man

Abstract

Sulpiride (SU), a widely used benzamide neuroleptic, is known to promote rapid prolactin release. Sulpiride plasma level and the prolactin response to the most commonly used dose, i.e., 50 and 200 mg sulpiride (administered orally), were studied in ten male volunteers.The design of this study permitted the simultaneous measurement of the sulpiride plasma level for 48 hours, by means of a new HPLC-electrochemical detection method, and of the prolactin level, by means of RIA.Pharmacokinetic study of sulpiride showed that the mean concentration and time of peak plasma level of the two doses were different: 77 ng/rnl SV at 2.3 h for the 50 mg dose and 243 ng/ml at 3.5 h for the 200 mg dose. The absorption and elimination rate constants were similar regardless of the dose (k a: 1.05-1.9 h -I; t 1;2~: 25 h).. A linear relationship of the area under the plasmatic concentration versus time curve with the dose was observed. Mean plasma level decreased for both doses to about 14% of peak value at 48 hours.Prolactin serum levels increased from the basal value after SU administration with marked individual differences. The 200 mg dose resulted in earlier prolactin peak levels (54 ng/ml between 30 min and I h) than the 50 mg dose (50 ng/ml between I and 2 h). The prolactin level then decreased and remained constant at about 15 ng/ml for II to 48 h. Prolactin levels returned to basal values (mean: 5 ng/ml) after one week.It is concluded that therapeutic doses of sulpiride induce prolactin secretion that is dose-dependent in a first phase and stimulated independently of the sulpiride concentration in a second phase. A mechanism of indirect action mediated by PRL is suggested to explain the neuroleptic activity of the drug.

Influence of the dosing interval on prolactin release after remoxipride.

“…The peak plasma prolactin levels (Cmax,PRL) have been reported to be dose-related up to a maximal release following administration of remoxipride [13,14,29], sulpiride [16,[21][22][23][24][25] and also following TRH [26,27]. Maximal prolactin peak concentrations are expected to be achieved with the doses of remoxipride and TRH administered in the present study [26,27].…”

Paradoxical dopaminergic drug effects in extraversion: dose- and time-dependent effects of sulpiride on EEG theta activity

“…In a nutshell, there is a dose-dependent biphasic action that relates to the balance of pre- to postsynaptic effects (50 mg > 200 mg presynaptic vs. 400 mg postsynaptic predominance). In addition, pharmacokinetic data showed that within the tuberoinfundibular system the maximal prolactin response to 50 and 200 mg are time shifted (Sugnaux et al, 1983): the response to 50 mg sulpiride occurrs1 h later compared to 200 mg. Thus, postsynaptic effects rush in or dominate later in time for low compared to high doses.…”

“…In the same vein, a decreased striatal activation to reward seen with 400 mg sulpiride is in keeping with the hypothesis that inhibition of dopamine transmission (via postsynaptic effect) predominates 400 mg sulpiride (McCabe et al, 2011). In addition, the maximal prolactin response to 50 and 200 mg are time shifted (Sugnaux et al, 1983): the response to 50 mg sulpiride occurred 1 h later compared to 200 mg. Thus, the postsynaptic effects dominate later in time for low compared to high doses and consequently, presynaptic effects had to peak earlier in time for high compared to low doses.…”

Methylphenidate Has Differential Effects on Blood Oxygenation Level-Dependent Signal Related to Cognitive Subprocesses of Reversal Learning

“…Dose selection was based on previous, similar studies showing behavioral effects at similar (and lower) doses using the same drugs in healthy volunteers (Mehta et al, 1999(Mehta et al, , 2000Volkow et al, 2002). The timing of fMRI testing was performed at approximately the time of maximal plasma levels of both drugs based on pharmacokinetic data (Sugnaux et al, 1983;Wagstaff et al, 1994;Kimko et al, 1999).…”