Drug-Metabolizing Enzymes and Praziquantel Bioavailability in Mice Harboring Schistosoma Mansoni Isolates of Different Drug Susceptibilities

Abstract

The level of drug-metabolizing enzymes (cytochrome P450 [CYP450] and cytochrome b5 [cyt b5]) and the bioavailability of praziquantel (PZQ) were investigated in batches of mice infected with Schistosoma mansoni displaying either a decreased susceptibility to PZQ ("EE2" and "BANL"-isolates), or a normal susceptibility to the drug ("CD" isolate). Each batch was divided into 2 groups. The first group was further subdivided into 5 subgroups. Subgroups 1 to 4 were treated 7 wk postinfection (PI) with oral PZQ at 25, 50, 100, and 200 mg/kg for 5 consecutive days, whereas the fifth subgroup was administered the vehicle only as control. Animals were perfused 9 wk PI, and worms were counted to estimate PZQ ED50. CYP450 and cyt b5 were examined in hepatic microsomes of infected untreated mice and of infected mice treated with 25 and 200 mg/ kg PZQ. The second group was given PZQ 7 wk PI and was further subdivided into 11 subgroups, killed at 2, 5, 15, 30, 60, 90, 120, 150, 180, 240, and 360 min postdosing to study pharmacokinetic parameters of PZQ. Mice harboring S. mansoni isolates having higher PZQ ED50 (170.3 mg/kg for EE2 and 249.9 mg/kg for BANL vs. 82.96 mg/kg for CD) had higher levels of CYP450 and cyt b5, a PZQ Cmax decreased by 19-30% and area under the serum concentration-time curve0-6 hr decreased by 57-74%. Data suggest that S. mansoni isolates that are less sensitive to PZQ induce a lower inhibition of hepatic drug-metabolizing enzymes, with a consequently higher metabolic transformation of PZQ.

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

“…The heavy inflammation of the gut wall that was observed microscopically might result in decreased drug absorption, which could be an explanation for this finding. It is interesting to note that, contrary to our findings, increased C max values were determined for praziquantel in infected rodents (8).…”

“…Furthermore, the estimated AUC is 2-fold higher in infected animals than in noninfected mice for both drugs. The slow clearance of both drugs might be attributed to a decreased activity of the cytochrome P450 enzyme system caused by the S. mansoni infection (8). It is known that the AUC and the elimination half-life of mefloquine in humans are significantly increased by inhibition of CYP3A4 with inhibitors (e.g., ketoconazole) (Lariam information leaflet).…”

“…Oral formulations of enpiroline and mefloquine were prepared 3 h before treatment as water-based suspensions in 7% (vol/vol) Tween 80 and 3% (vol/vol) ethanol. Groups of mice (n ϭ 3 per group) were treated orally with 200 mg per kg of body weight of enpiroline or mefloquine by gavage and sacrificed by the CO 2 method at selected time points posttreatment (1,2,4,8,12,24,48,72, or 168 h). Whole-blood samples of 0.5 to 1 ml were collected by cardiac puncture of each mouse.…”

“…The onset of action was determined at different time points following treatment with single oral doses of enpiroline and mefloquine administered to mice (n ϭ 3 per group). After each PK sampling point (1,2,4,8,12,24,48,72, or 168 h posttreatment), the liver and gut, including the portal vein and mesenterial veins, were dissected from infected mice. Livers were pressed and examined under the microscope, and all worms were sexed and counted (16).…”

“…In addition, PK studies undertaken with praziquantel in S. mansoni-infected mice documented elevated plasma levels in infected animals compared to the plasma levels in noninfected mice. Furthermore, the infection resulted in significant inhibition of microsomal cytochrome P450 activities compared with those in noninfected mice (8).…”