The tolerance of Praziquantel (2-cyclohexylcarbonyl-1, 3, 4, 6, 7, 11b-hexahydro-2H-pyrazino-[2, 1-a]isoquinoline-4-one) in oral doses of 1 X 20 mg/kg, 1 X 50 mg/kg, 3 X 10 mg/kg and 3 X 25 mg/kg body weight (tau = 4 h) was tested in a complex study involving 36 healthy volunteers. In addition to the usual assessment of clinical chemistry, haematology, coagulation physiology, urinalysis, clinico-physiological examination including EEG, and medical examination, clinico-psychological parameters were also recorded and special neurological investigations were performed. No clinically relevant changes were found in any of the laboratory parameters, nor in the medical-neurological or clinico-physiological examinations. Based on a few clinico-psychological parameters and subjective comments, the largest daily dose tested (3 X 25 mg/kg = 75 mg/kg) produced a slight, transient disturbance in general well-being, which was barely detectable on objective clinical examination. The pharmacokinetic behaviour was dominated by rapid metabolism and pronounced first-pass metabolism of praziquantel, which greatly limits the value of results obtained by GC analysis of unchanged drug in serum. The peak concentration in serum was reached after 1--2 h, and the elimination half-life for the period 2--8 h was 1--1.5 h.

The pharmacokinetics of 14C-praziquantel were tested in various species. Intravenously injected praziquantel is rapidly absorbed by the tissues in all species. The sum of unchanged drug and metabolites is rapidly eliminated from the intravascular space at a half-life of 3 hours (phase I) and 8 hours (phase II). The elimination for praziquantel itself, however, is considerably shorter, i. e. about 1 hour.After oral administration praziquantel was almost completely absorbed from the gastro-intestinal tract. Maximum serum concentrations were already reached within 30 min. to 1 hour. In rats absorption of the drug already from the stomach was observed.Non-metabolised praziquantel shows-due to an intense first pass effect in the liver-only very low maximum serum concentrations.All the species examined excrete the drug and its metabolites rapidly: within only 24 hours after administration the main portion of the administered HC-radioactivity was recovered in the excretion products. The kidneys are the predominant elimination path for praziquantel,The percentage of radioactivity eliminated with the bile in rats was 37 %of the dose within 7 hours after i. v, injection and 15 % of the dose after oral administration.Determination of the protein binding showed that 4(5 of the praziquantel is reversibly bound to serum proteins.

The metabolism of Praziquante1 in man was studied after po. administration of 44 mg/kg and 14 mg/kg 14C-Praziquante1 to male and female subjects. Thin layer chromatography of the radioactive constituents in serum and urine showed that Praziquante1 is rapidly metabolized in man. Already 4 hrs after po. administration -the time of maximum serum-radioactivity -the amount of unchanged drug is less than 5% of the serum-radioactivity. No unchanged drug was found in the urine. the major route of elimination of radioactivity.The major metabolites in serum and urine were isolated and subjected to mass spectrometry. According to their mass spectra they are predominantly hydroxylation products of Praziquante1, containing one or two hydroxy groups. The metabolism of Praziquante1 in man appeared to be both independent of sex and dose in the dose range studied.In vitro studies with rat liver homogenates showed that the metabolism of Praziquantel can be induced by phenobarbital. As in in vivo experiments the metabolites formed in vitro are hydroxylation products of Praziquantel.

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