Factors Affecting the Pharmacokinetics, Metabolism and Efficacy of Anthelmintic Drugs

Benchaoui, Hafid Abdelaali (1994) Factors Affecting the Pharmacokinetics, Metabolism and Efficacy of Anthelmintic Drugs. PhD thesis, University of Glasgow.

Abstract

The plasma disposition of albendazole, albendazole sulphoxide, and netobimin were investigated in goats following oral administration at the dose rate of 7.5 mg/kg. Netobimin and albendazole were not detectable at any time following drug administration. Plasma levels achieved by the anthelmintically active metabolite, albendazole sulphoxide (ABSO), were not significantly different following administration of albendazole (AUC= 54.40 mug.h/m1; Cmax= 2.38 mug/ml) and albendazole sulphoxide (AUC= 63.04 mug.h/ml; Cmax= 2.77 mug/ml). Following administration of netobimin, the AUC and Cmax for ABSO were 29.76 mug.h/m1 and 1.35 mug/ml, respectively. The effect of the metabolic inhibitor, piperonyl butoxide (administered intramuscularly at 0.5 g/kg bodyweight), on the pharmacokinetics of albendazole (in sheep and goats) and fenbendazole (in goats) was studied. It was found that in sheep, pretreatment with piperonyl butoxide increased the area under the curve (AUC) and the mean residence time (MRT) of albendazole sulphoxide by 77% and 50%, respectively. The AUC and MRT of albendazole sulphone were also significantly increased with piperonyl butoxide pretreatment. In goats, the pharmacokinetic parameters of ABSO were not significantly increased by piperonyl butoxide. Pretreatment of goats with the inhibitor caused more than three-fold increases in the bioavailability of fenbendazole (FBZ) and fenbendazole sulphoxide (FBSO). The plasma disposition of piperonyl butoxide was determined in sheep and goats. Peak plasma concentrations were achieved between 10 and 15 hours. In sheep, the AUC and Cmax were 132.96 mug.h/m1 and 2.92 mug/ml, respectively. In goats, the AUC and Cmax amounted to 82.10 mug.h/ml and 1.17 jag/ml, respectively. A pharmacokinetic dose titration study was carried out with fenbendazole and piperonyl butoxide in sheep. Fenbendazole was given at a fixed dose (5 mg/kg) and piperonyl butoxide was administered orally at 0, 15, 31, 63, 125 and 250 mg/kg. The AUC of fenbendazole (FBZ) and fenbendazole sulphoxide (FBSO) increased significantly with dose rates of piperonyl butoxide equal to or higher than 31 mg/kg. Peak plasma concentrations (Cmax) and mean residence times (MRT) were also significantly increased with the coadministration of fenbendazole and piperonyl butoxide. Piperonyl butoxide given orally to two sheep was well absorbed resulting in an AUC of 761.2 mug.h/m1 (sheep 95) and 538.4 mug.h/ml (sheep96). The efficacy of the combination fenbendazole-piperonyl butoxide (FBZ-PB) was assessed in sheep against benzimidazole-resistant Ostertagia circumcincta and Haemonchus contortus. T h e percentage reduction in the total number of O. circumcincta worms was 7.90% (FBZ alone) and 97.8% (FBZ-PB). For Haemonchus contortus, the percentage reduction was 84.8% (FBZ alone) and 99.0% (FBZ-PB). Reduction in the faecal egg output, 7 days after treatment was 93.7% (FBZ alone) and 99.6 % (FBZ-PB). Piperonyl butoxide, given alone, had no effect against these two nematode species. The in vitro metabolism of fenbendazole, oxfendazole, albendazole preparations and and triclabendazole was studied using microsomal cultured hepatocytes from rat liver. The extent of metabolism was found to be in the order triclabendazole > albendazole > fenbendazole and oxfendazole. Piperonyl butoxide inhibited the S-oxidation of all the benzimidazole drugs studied. 1-aminobenzotriazole inhibited significantly the metabolism of triclabendazole in hepatocyte cultures. The effect of the salicylanilide compound rafoxanide against immature (4 week-old) stages of Fasciola hepatica was investigated in artificially infected sheep. Antipyrine clearance tests together with plasma glutamate dehydrogenase (GLDH) and gamma-glutamyl transferase (mugT) activities were used to follow the evolution of flukicidal therapy with rafoxanide. Glutamate but increased again at 12 weeks post-infection in the infected rafoxanide-treated sheep (group B). In the infected untreated sheep (group A), Antipyrine clearance decreased between 8 and 14 weeks post-infection. In the infected treated sheep (group B), plasma clearance of antipyrine remained unchanged until 10 weeks after rafoxanide treatment when it decreased from the pre-infection value of 5.09 to 3.90 ml/min.kg. Rafoxanide did not alter antipyrine disposition in uninfected sheep (group C).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Quintin A McKellar
• Keywords: Pharmacology
• Date of Award: 1994
• Depositing User: Enlighten Team
• Unique ID: glathesis:1994-74672
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Sep 2019 17:14
• Last Modified: 27 Sep 2019 17:14
• URI: https://theses.gla.ac.uk/id/eprint/74672