Disposition of mefloquine and enpiroline is highly influenced by a chronic 1 Schistosoma mansoni infection

21 Chronic Schistosoma mansoni infections lead to severe tissue destructions of the gut wall 22 and liver and can influence drug disposition. This study aimed to investigate the impact of a 23 chronic S. mansoni infection on pharmacokinetic (PK) parameters of two promising 24 antischistosomal lead candidates (mefloquine and enpiroline) in mice. Studies were 25 conducted in two different mouse cohorts (S. mansoni-infected and non-infected mice) for 26 both drugs. Plasma samples were collected after oral treatment (200 mg/kg) with study drugs 27 at various time points. An HPLC method was validated to analyze enpiroline and mefloquine 28 in plasma. Livers and intestines were collected from infected animals to determine the onset 29 of action, hepatic shift and worm burden reductions. Following mefloquine administration 30 hepatic shifting and significant worm burden reductions (79.2%) were observed after 72 h. 31 The majority of worms had migrated one week post treatment with enpiroline to the liver and 32 significant worm burden reductions were observed (93.1%). The HPLC-method was 33 selective, accurate (87.8 111.4%) and precise (<10%) for the analysis of both drugs in 34 plasma samples. PK profiles revealed increased half-lives and AUCs for both drugs in 35 infected animals when compared to uninfected animals. Considerable changes were 36 observed for mefloquine with a 5-fold increase of t1/2 (182.7 h versus 33.6 h) and 2-fold 37 increase of AUC (1116517.8 ng*h/mL versus 522409.1 ng*h/mL). 38 S. mansoni infections in mice influence the PK profiles of enpiroline and mefloquine leading 39 to delayed clearance. Our data confirm that drug disposition should be carefully studied in 40 schistosomiasis patients. 41 42 on D ecem er 0, 2017 by gest httpaac.asm .rg/ D ow nladed fom