Pharmacokinetics and relative bioavailability of praziquantel in healthy water buffalo after oral and intramuscular administration.

摘要

Praziquantel(PZQ)[2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline-4-0ne] is a member of acylated isoquinoline-pyrazine (Fig. 1) used in the treatment for schistosomiasis caused by all schistosoma species pathogenic to domestic animals, especially bovines (water buffaloes and cattle) (Thomas & Gonnert, 1977). Schistosomiasis is a zoonosis of major public health importance in southern China, where one million people are infected by this disease (Guo & Li, 2006). Water buffalo are major reservoirs for human schistosomiasis infection in the marshlands? lake areas, and they play an important role in the transmission and epidemiology of the disease to human in China (Guo & Li, 2006), and therefore, control of water buffalo schistosomiasis has the important meaning to the human health. In the absence of a readily available vaccine used in the treatment for water buffalo schistosomiasis, chemotherapy is the recommended strategy with praziquantel used as drug to treat schistosomiasis (Gryseels, 2000). Other chemotherapy medicines (nitrofurans, nithiocyanamine, and niridazole) are also used to treat water buffalo schistosomiasis, but the treatment result is inferior to the praziquantel (Osvaldo & Edymar, 1992; Gonnert & Andrews, 1977). Currently, the market supply of dosage forms are various tablets of praziquantel. It has been shown that praziquantel is completely absorbed in the GI tract in almost all species studied, but there is an extensive hepatic ?rst-pass effect of praziquantel after oral administration in ruminants (cattle, goats, and water buffaloes) (Cao et al., 2001; Jia et al., 2001), and liver oxidative metabolism of praziquantel yields hydroxylated metabolites via CYP-dependent metabolism which led to praziquantel parent drug concentrations are low in the bloodstream compared with the i.m. treatment. For instance, a CYP3A isoenzyme was found to be involved in praziquantel hydroxylation in sheep liver, and praziquantel can be metabolized to 4-hydroxypraziquantel in animals (sheep, rats, and water buffaloes) (Collen & Julia, 1994), so there is a lower systemic availability and lower concentration in the bloodstream of parent drug after oral administration compared with the i.m. treatment (Stelma et al., 1995; Cao et al.,2001). In view of this reason, there is a clearly need for research and development of novel praziquantel injection dosage forms or to make more effective use of existing ones. A 20% praziquantel injection is a new preparation, which was developed by Shanghai Veterinary Research Institute, CAAS. This formulation has the potential to become a valuable antiparasitic agent in the treatment for water buffaloes schistosomiasis. The tissue concentrations and pharmacokinetics of praziquantel injection at 10 mg ?kg in cattle has been studied (Cao et al., 2001), but the disposition kinetics of the drug in water buffalo has not been fully documented. The main objective of this work was to evaluate the plasma kinetic disposition of praziquantel after its i.m. (10 mg ?kg) and oral (30 mg ?kg) administrations to water buffaloes.