[Involvement of cytochrome P4503A in the monohydroxylation of ring A of praziquantel in rat liver microsomes].

The possibility of involvement of cytochrome P4503A (CYP3A) in the monohydroxylation of the ring A of praziquantel (PZQ) was studied by using CYP3A specific inducer dexamethasone (DEX), specific inhibitor triacetyloeandomycin (TAO) and the activity of erythromycin (ERY) and ethylmorphine (EMP) N-demethylase which are known to be marker for CYP3A enzyme activity as probes. In the liver microsomes obtained from rats pretreated with CYP3A inducer DEX with TAO treatment the content of uncomplexed P450 was decreased, the activity of ERY and EMP N-demethylase ws reduced, and simultaneously, the rate of formation of ring A monohydroxylate of PZQ was inhibited. Ring A monohydroxylate formation was competitively inhibited by TAO and ERY. The rates of ring A monohydroxylate formation were strongly correlated with the activity of N-demethylase of ERY and EMP. These results indicate that CYP3A is involved in the monohydroxylation of the ring A of PZQ.

Levo-praziquantel versus praziquantel in experimental and clinical treatment of schistosomiasis japonica.

Levo-praziquantel is the left isomer of racemic praziquantel. Animal experiments showed that it is an active component of schistosomicidal activity, while dextro-praziquantel is almost ineffective. Clinical trials in three endemic areas of Schistosomiasis japonica indicated that the therapeutic efficacy of levo-praziquantel is superior to racemic praziquantel. Pharmacokinetic and pharmacodynamic activities of the stereoselectivity of praziquantel isomers (enantiomers) are discussed.

[Cytochrome P450 monooxygenase contents and activities in human liver microsomes prepared from Chinese adults].

Seven human liver samples were collected in this study. Five of them were obtained from donors died from non-disease accident, one was taken from part of the normal tissue of a liver specimen obtained by partial hepatectomy in a case of hepatic cavernous hemangioma and the last one from postmortem died by road accident. All the liver pieces were stored at -75 degrees C immediately after removed from the body. Liver microsomes was prepared by differential ultracentrifugation. The contents of cytochrome P450 and cytochrome b5 in Chinese adult liver microsomes were 0.36 +/- 0.08 and 0.23 +/- 0.05 nmol.mg-1 protein (n = 7). The activities of aminopyrine and ethylmorphine N-demethylase, 7-ethoxycoumarin-O-deethylase, nifedipine oxidase and (-)-praziquantel hydroxylase were 1.07 +/- 0.23, 1.82 +/- 0.31, 0.30 +/- 0.10, 0.43 +/- 0.18 and 0.69 +/- 0.43 nmol.mg-1.min-1 (n = 7), respectively.

[The stereoselective binding of praziquantel enantiomers to plasma proteins].

The stereoselective binding of praziquantel (PQT) enantiomers to plasma proteins was studied by equilibrium dialysis. The binding of (+/-)-PQT and its enantiomers to bovine serum albumin (BSA) and rabbit plasma was unsaturable when initial drug concentrations from 1 to 32 mumol/L were used. The binding capacity (nK) of (+/-)-PQT to BSA (1.47 or 5.88 x 10(-4) mol/L) was greater than that of (-)-PQT with a (+)-/(-)-PQT ratio of 1.25 or 1.26, respectively. However, the preferential binding of (-)-PQT to rabbit plasma was found to be 73.7 +/- 4.4% for (-)-isomer and 58.3 +/- 10.1% for (+)-isomer (n = 8, P less than 0.05). The binding of (+)- and (-)-PQT to human plasma was 81.9 +/- 4.2% and 83.2 +/- 6.9% (n = 10, P greater than 0.05) respectively, which seems to be not stereoselective. These results indicate that there are species differences in the stereoselective binding of PQT enantiomers to plasma proteins.

[Stereoselectivity of arrhythmogenic effect of praziquantel in conscious rabbits].

Praziquantel (PQT) is a chiral compound with an asymmetric center at the 11 b-position. The recemic mixture is usually used as an antischistosomal drug, however the antischistosomal activity is mainly concentrated in the R (-)-enantiomer. This study was undertaken to investigate the stereoselectivity of the arrhythmogenic effect of PQT in conscious rabbits. Arrhythmias, as well as bradycardia, were induced in rabbits by iv (+/-) PQT or its enantiomers at 45 mg/kg. The frequency of ectopic rhythms in the (+), (+/-) and (-) PQT groups were 100, 60 and 20%, respectively. Statistically, the frequency of ectopic rhythms in the (+) PQT group was significantly higher than those in the (-) PQT group and in the (+/-) PQT group, although there was no significant difference between the (+/-) and (-) PQT groups. The severity of the arrhythmias induced by (+) PQT was much higher than that induced by (-) PQT. The bradycardia action of (+) PQT was much more intense than that of (-) PQT. (+/-) PQT or its enanthiomers (icv) at a dose of 2 or 3 mg/kg also induced arrhythmias. The frequency of ectopic rhythms in the (+) PQT group was significantly higher than that in the (-) PQT group. The results suggest that there is a stereoselectivity of the arrhythmogenic effects of PQT in rabbits. Arrhythmias induced by PQT may partly mediated via the central nervous system, and the arrhythmogenic effects of (+/-) PQT may be caused mainly by (+) PQT.

[The liver first pass effects and bile concentrations of (-)-, (+)- and (+/-)-praziquantel in rabbits].

Praziquantel (PQT) is a racemic mixture. Intragastric gavage of (-)-, (+)- and (+/-)-PQT 100 mg/kg were used to study the liver first pass effects in rabbits. HPLC was used to determine the concentration of each compound in the portal and systemic circulation, and in the bile within 4h. The results showed that all drugs were absorbed rapidly from the gut into the portal vein. The serum concentration in the portal vein were similar. However, over 90% of PQT and its enantiomers were extracted in the first passage through the liver. Intrinsic metabolic clearances of the liver of (-)-, (+)- and (+/-)-PQT were 50.3, 174.4 and 52.6 L/h, respectively. The serum concentrations of the three drugs markedly decreased in the systemic circulation, especially that of (+)-PQT. The AUC of (+)-PQT was apparently lower than that of (-)- or (+/-)-PQT. From these results, it is assumed that the first pass effects of PQT and its enantiomers in the liver are pronounced and most likely stereoselective. Also, unchanged PQT and its enantiomers were found in the bile of the rabbits.