A. Benakis

Localization, distribution, elimination and metabolism of14C-Sulpiride in rats

SummaryThe localization, distribution, elimination and metabolism of14C-Sulpiride administered in doses of 20 mg/kg by i. p. and oral route in rats is described. Whole-body autoradiography and quantification in organs and tissues as a function of time showed that the distribution of radioactivity throughout the body is general with the highest level in the kidineys, pelvis, liver and hypophysis 1 hour after administration. The blood radioactivity level reaches its maximum 5 minutes after i. p. administration with a value of 11 μg/ml, of which 85 % is due to unchanged Sulpiride. At later determinations, the amount drops to 60–65 % of unchanged Sulpiride. In the bile, the maximum radioactivity is measured between 1 and 1 hour 1/2 in either extra-corporal circuit or choledocal fistula. After i. p. administration, urinary elimination is an average of 64 % of the administered dose in 72 hours, of which 70 % to 55 %, depending on the period, is due to unchanged Sulpiride. Fecal elimination after i. p. administration is an average of 26 % of the administered dose in the 72 hours period. Conversely, after oral administration, urinary elimination represents an average of 18 % of the administered dose in 72 hours and fecal elimination represents an average of 74 % for the same period. Aside from the unchanged product, 7 to 8 metabolites were separated and quantified at the plasmatic, urinary and biliary level. Very low amounts of radioactivity were recovered as14CO2 indicating that the labelled position is very stable.

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

SummaryResults 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-pyrrohdinyl)methyl]-2-hydroxybenzamide (in rat only), 5-amtaosulfonyl-N-[(2-pyrroBdlnyl)methyl]-2-hydroxybenzamide,5-anunosulfonyl-N-[(l-ethyl-5-oxo-2-pyrroUdin zamide, 5-aminosulfonyl-2-methoxybenzamide, 5-aminosulfonyl-N-[(l-ethyl-5-oxo-2-pyrrolidinyl)methyl)-2-methoxybenzamide,5-aminosulfonyl-N-[(2-pyrrolidinyl)methyl]-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.

Plasma Concentrations of Laudanosine, but Not of Atracurium, Are Increased during the Anhepatic Phase of Orthotopic Liver Transplantation in Pigs

To quantify the changes in plasma concentrations of atracurium and laudanosine induced by the lack of hepatic function and circulation, the authors studied nine domestic pigs (22-25 kg) undergoing an orthotopic liver transplantation, and three control animals without surgery, using atracurium as the muscle relaxant. After intubation facilitated by isoflurane 2-3%, anesthesia was maintained with isoflurane (0.5% in oxygen) and fentanyl (4 micrograms.kg-1.hr-1). Ventilation was controlled to keep end-tidal CO2 at 35-40 mmHg, body temperature maintained at 35.5-37.5 degrees C, and arterial pH at 7.35-7.50. The right sciatic nerve was stimulated with a nerve stimulator delivering a single twitch at 0.1 Hz with 0.2-ms duration, at supramaximal stimulation. The force of the corresponding evoked isometric muscle contraction was continuously measured by a force-displacement transducer. A single iv bolus of atracurium (2 mg/kg) was given to obtain a 90-95% twitch depression, followed 5 min later by a constant-rate iv infusion of atracurium at 120 micrograms.kg-1.min-1 maintained during the entire investigation. Blood samples for plasma atracurium and laudanosine concentrations were drawn every 15 min. In the control group, plasma concentrations of atracurium remained stable between 6.5-8.0 micrograms/ml following initial bolus injection; plasma concentrations of laudanosine increased during the first 60 min, then remained stable between 0.69-0.74 micrograms/ml up to the end of the study. In animals undergoing transplantation, plasma concentrations of atracurium remained stable between 10-12 micrograms/ml, despite a 90-min duration of liver exclusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Vecuronium neuromuscular blockade reflects liver function during hepatic autotransplantation in pigs

BackgroundRapid assessment of hepatic function early after reperfusion of the liver graft is of great importance, because it may allow for prompt detection of incipient hepatic graft failure. The current study was undertaken to determine whether the continuous recording of neuromuscular transmission could be used as an on-line assessment of hepatic function during liver transplantation when a muscle relaxant with high hepatic uptake is used. MethodsWe quantified and compared the effect of liver exclusion and graft reperfusion on the level of vecuronium-induced neuromuscular blockade in nine pigs studied twice within 3 days. During the 1st day (control session), an intravenous infusion of vecuronium was administered to maintain a constant 90–95% twitch depression during 180 min. The twitch response was then allowed to recover spontaneously to 75% of its prerelaxant value. Neuromuscular transmission was continuously measured on the right anterior leg using an acceleration transducer. During the same time period, the metabolic rate of 14C-labeled aminopyrine (a well-established quantitative test of the liver microsomal function) was determined by measuring the excretion of 14CO2 in expired air after administration of an intravenous bolus of 14C-labeled aminopyrine. Two days later, the pigs underwent a hepatic autotransplantation, during which vecuronium was administered to maintain a constant 90–95% twitch depression. After reperfusion of the liver graft, the vecuronium Infusion rate was maintained at its anhepatic level, and the recovery index of the neuromuscular blockade (the time from 25% to 75% recovery of twitch height) was calculated. The aminopyrine breath test was performed during the last 30 min of the anhepatic phase, and during 3 h after reperfusion of the liver graft. ResultsDuring control studies, the mean infusion rate of vecuronium was 1.30 ± 0.33 mg · kg-1 · h-1 and the recovery index was 3.4 ± 0.5 min. During liver dissection, the infusion rate of vecuronium was similar to the control value (1.18 ± 0.16 mg · kg-1 · h-1), then considerably decreased to 0.05 ± 0.03 mg · kg-1 · h-1 during the anhepatic phase. After reperfusion of the liver graft, the recovery index was markedly prolonged to 35.5 ± 15.8 min, indicating a prolongation of the recovery of neuromuscular blockade by a factor of 10.4. Excretion of 14CO2 was equal to zero during the anhepatic phase and then increased to 0.19 ± 0.11% during the 1st h after reperfusion of the liver graft, an excretion rate corresponding to 11.2% of control conditions. The relationship between individual changes in the recovery index of the neuromuscular blockade and 14CO2 excretion in expired air after reperfusion of the liver graft showed a strong significant correlation (r = 0.71). ConclusionsThese results indicate that, compared with the control studies, there is a similar decrease in the recovery rate of vecuronium-induced neuromuscular blockade and in the metabolic rate of 14C-labeled aminopyrine during the progressive recovery of hepatic function Immediately after un-clamping of the liver vessels. Metabolism of 14C-labeled aminopyrine increased progressively during the reperfusion phase. Therefore, recording of neuromuscular transmission during liver transplantation could serve as a continuous and easy to perform assessment of liver graft function provided that a muscle relaxant with a high hepatic uptake is used for neuromuscular blockade.

Pharmacokinetics of arteether in dog

SummaryA pharmacokinetic study has been conducted in six beagle dogs after i.m. administration of 25 mg/kg of arteether, a qinghaosu (artemisinin) derivative of high anti-malarial activity.Arteether plasma concentrations were measured during a 24 h period using HPLC with an electrochemical detector in the reductive mode. The pharmacokinetic parameters were established using an open two-compartment model.Results showed a relatively rapid absorption phase: T1/2ka was 0.300 ± 0.096 h and a mean elimination half-life of 27.95 ±11.93 h. Cmax was 110 ± 16 ng/ml, Cltot/F was 1.69 ± 0.34 ml/min and AUC was 2797 ± 476 ng/ml/h.

Pharmacokinetics/Pharmacodynamics findings after repeated Administration of ARTESUNATE thermostable suppositories (RECTOCAPS) in Vietnamese patients with uncomplicated malaria

SummaryIn recent years, Artemisinin and particularly one of its derivatives — Artesunate (ART — has become an essential alternative for treatment of both uncomplicated and severe falciparum malaria in Asia and Africa as well.Therefore, these compounds are still and inccreasingly in the focus of interest because of quick acting of this drug, is able to help even unconscious to overcome the malaria attack, when administered by injection. As an alternative, RECTOCAPS have been developed and their use is meanwhile well established. From earlier studies in children, suffering from Plasmodium falciparum malaria, we obtained a high level of DHART in the blood, but as expected also a rapid decline in the levels of both DHART and ART. A second administration of ART was additionally applied 4 hours after the first administration. DHART and ART plasma levels were found to last longer on an assumed therapeutic level than those obtained after one administration only. The fever clearance and the parasitemia reduction rates were found to be effective according to this dosing regimen. In view of these findings, we decided to conduct the actual described study by administering 200 mg of ART every 3 hours (0, 3, 6 and 9 h) by the rectal route.Soft geiatine capsules (RECTOCAPS) containing 200 mg of ART GMP — type each (Artesunic acid) were administered by rectal route. Each patient received four RECTOCAPS capsules (4×200 mg of ART) over a 3 h period.12 adult patients with uncomplicated malaria were selected. Age, weight, height, body temperature, parasite counts before treatment and their evolution until 96 h are determined. Blood samples were taken at short time intervals after starting with the first medication: 0, 30 min, 60 min, 3 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h, 84 h, 96 h and 108 h. The aliquots of all the blood samples were used for performing parasite counts. Plasma obtained following the traditional procedure was kept at −40°C until analysis. HPLC technique with electrochemical detector was used for quantification of ART and DHART. From the blood concentration values of ART and DHART, the following observation can be derived: the onset of action is observed within the first half hours, therapeutic levels of the drug obtained (89 μg/ml ART compared to 84 μg/ml DHART). The DHART levels are somewhat higher than those of ART (a peak concentration after 6 h starting medication of 151 μg/ml ART as compared to 276 μg/ml DHART). The variations as a function of frequency of DHART uptake are much less marked than those observed for ART. Another finding is that after the administration, some sort of a plateau of DHART and ART is built up, lasting at least from 9 to 12 hours with DHART level of about 190 μg/ml and ART of 90 μg/ml. In the case of single-dose administration, the levels of both compounds were below the detection threshold after three hours.With regard to the parasite counts, although there were inter-individual variations, it should be noted that after 48 hours a high proportion of the patients (8 out of 12) was completely clear of parasites. Similar results were observed with regard to the body temperature (7 out of 12 returned to normal temperature 36 hours after starting the therapy). The findings of the study support the RECTOCAPS application principle resulting in effectiveness both for the velocity of drug uptake as well as for the height of plasma levels. Repeated administration of ART can extend the duration of therapeutic plasma levels of the drug.

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

SummarySulpiride (SU), a widelyused benzamide neuroleptic, is known to promote rapid prolactin release. Sulpiride plasmalevel and the prolactin response to the most commonly used dose, i.e., 50 and 200 mg sulpiride (ad-ministered orally), were studied inten 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/ml SU at 2.3h for the 50 mg dose and 243 ng/ml at 3.5 h for the 200 mg dose. The absorption and elimination rateconstants were similar regardless of the dose. (ka: 1.05–1.9 h−1; t1/2β: 25 h).. A linear relationship of the area underthe plasmatic concentration versus time curve with the dose was observed. Mean plasma leveldecreased for both doses to about 14%of peak value at48 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 1 h) than the 50 mg dose (50 ng/ml between 1 and 2 h). The prolactin level then decreased and remained constant at about 15 ng/ml for 11 to 48 h. Prolactin levels returned to basal values (mean: 5 ng/ml) after one week.It is concludedthat therapeutic doses of sulpiride induce prolactin secretion thatis 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 explainthe neurolepticactivityofthe drug.

Autoradiographic study of14C-Sulpiride in monkey

SummarySubstituted benzamides have been the object of numerous metabolic studies including many by whole body autoradiography of rats and mice.The present study reports autoradiographic data concerning14C-labelled Sulpuride in monkey. The Study was limited to the brain in order to elucidate the controversial question as to whether the drug can cross the blood-brain barrier. The results showed that in monkey, as in rat and mouse, there is no localization in the brain as can be clearly seen on the autoradiograms. In view of these results and of the undeniable neuroleptic properties of Sulpiride, an indirect mode of action through the release of endogenous mediators is proposed.

Induction of hepatic microsomal enzymes by diuron, phenobenzuron, and metabolites in rats.

Microsomal liver enzymes are induced in rats which are fed a diet containing 1000 ppm of phenobenzuron, a phenylurea herbicide, for 7 days: All parameters measured are about 50% higher than control values. This increase is lower after 14 feeding days. Diuron and 3,4-dichloroaniline have a similar, although lower, effect than phenobenzuron. Two other metabolites have no action on microsomal enzymes. The transitory and weak inducing effect of these phenylureas is interesting when compared to other organochlorine pesticides.

Pharmacokinetics of atracurium besylate in the pig after a single i.v. injection.

SummaryA pharmacokinetic study of atracurium besylate was performed in the pig after a single i.V. bolus injection of 2 mg/kg, the dose needed to produce surgical neuromuscular blockade. The plasma concentration values were obtained by high performance liquid chromatography. Using a two-compartment pharmacokinetic model, the elimination half life was found to be 28.6±6.3 min (mean ± SEM), the total volume of distribution 341+56 ml/kg and the plasma clearance 8.7+1.1 ml/min/kg. Although the doses required to obtain a satisfactory neuromuscular blockade as well as the plasma level, volume of distribution and plasma clearance values were higher in the pig than in man, the distribution and elimination half-lives were similar to those recently reported.