Disposition of Mefloquine and Enpiroline Is Highly Influenced by a Chronic Schistosoma mansoni Infection

Abstract

cChronic Schistosoma mansoni infections lead to severe tissue destruction of the gut wall and liver and can influence drug disposition. This study aimed to investigate the impact of a chronic S. mansoni infection on the pharmacokinetic (PK) parameters of two promising antischistosomal lead candidates (mefloquine and enpiroline) in mice. Studies were conducted in two different mouse cohorts (S. mansoni-infected and uninfected mice) for both drugs. Plasma samples were collected at various time points after oral treatment (200 mg/kg of body weight) with study drugs. A high-performance liquid chromatography (HPLC) method was validated to analyze enpiroline and mefloquine in plasma. Livers and intestines were collected from infected animals to determine the onset of action, hepatic shift, and worm burden reduction. Following mefloquine administration, hepatic shifting and significant worm burden reductions (79.2%) were observed after 72 h. At 1 week posttreatment with enpiroline, the majority of worms had migrated to the liver and significant worm burden reductions were observed (93.1%). The HPLC method was selective, accurate (87.8 to 111.4%), and precise (<10%) for the analysis of both drugs in plasma samples. The PK profiles revealed increased values for half-life (t 1/2 ) and area under the concentration-time curve (AUC) for both drugs in infected animals compared to the t 1/2 and AUC values in uninfected animals. Considerable changes were observed for mefloquine, with a 5-fold increase of t 1/2 (182.7 h versus 33.6 h) and 2-fold increase of AUC (1,116,517.8 ng · h/ml versus 522,409.1 ng · h/ml). S. mansoni infections in mice influence the PK profiles of enpiroline and mefloquine, leading to delayed clearance. Our data confirm that drug disposition should be carefully studied in schistosomiasis patients.

Discovery and Characterization of Novel Anti-schistosomal Properties of the Anti-anginal Drug, Perhexiline and Its Impact on Schistosoma mansoni Male and Female Reproductive Systems

“…The dosing regimen used for the treatment with PHX was based on the recently reported pharmacokinetics (PK) of PHX in healthy C57BL/6 mice [ 30 ] and the consideration that a higher exposure could be potentially expected in infected animals. This hypothesis is in accordance with previously reported data showing an increased plasmatic concentration of PZQ and other schistosomicidal compounds in mice and humans infected with Schistosoma [ 40 – 42 ].…”

Schistosome infections induce significant changes in the host biliary proteome

“…Our results corroborate those reported by other authors for the liver and show that the elimination of drugs via both CYP and phase II of drug metabolism such as GST and UGT may be severely impaired during murine chronic schistosomiasis [35]. In fact, it has been demonstrated that chronic S. mansoni infection influence the pharmacokinetic profiles of some drugs, such as praziquantel, enpiroline and mefloquine, leading to delayed clearance [36,37]. Accordingly, given that schistosomiasis is prevalent in countries where coinfection for diseases such as HIV or malaria is common, it is important to ask how schistosomiasis affects the enzymes responsible for the metabolism of drugs given to treat not only schistosomiasis but also these coinfections [35].…”

Efficacy and Safety of Arachidonic Acid for Treatment of Schistosoma mansoni-Infected Children in Menoufiya, Egypt

“…Nevertheless, ARA schistosomicidal activity in experimental animals was faithfully reproduced in clinical trials at variance from mefloquine, which showed highly significant schistosomicidal action in mice and hamsters but poor efficacy in a randomized, exploratory human trial. [36][37][38][39][40] ARA seemed a far more promising schistosomicidal remedy than myrrh (Mirazid), which showed a low (10-15%) cure rate and low egg reductions in uncured individuals, regardless of the patients' ages or pre-treatment intensities of infection. [41][42][43] Despite that a 100% cure was reported after PZQ treatment of S. mansoni infections in eastern Sudan, 44 complete cures have seldom, if ever, been achieved in endemic areas after PZQ treatment.…”