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TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling.

ABSTRACT: Treatment of schistosomiasis relies precariously on just one drug, praziquantel (PZQ). In the search for alternatives, 15?S-[2-(alkylamino)alkane] thiosulfuric acids were obtained from a previous research program and profiled in mice for efficacy against both mature (>42-day-old) and juvenile (21-day-old) Schistosoma mansoni using a screening dose of 100?mg/kg PO QDx4. One compound, S-[2-(tert-butylamino)-1-phenylethane] thiosulfuric acid (TPT sulfonate), was the most effective by decreasing female and male worm burdens by???90% and ?46% (mature), and ?89% and ?79% (juvenile), respectively. In contrast, PZQ decreased mature female and male worm burdens by 95% and 94%, respectively, but was ineffective against juvenile stages. Against 7-day-old lung-stage worms, TPT sulfonate was only effective at twice the dose decreasing female and male burdens by 95 and 80%, respectively. Single oral doses at 400 and/or 600?mg/kg across various developmental time-points (1-, 7-, 15-, 21- and/or 42 day-old) were consistent with the QD x4 data; efficacy was strongest once the parasites had completed lung migration, and female and male burdens were decreased by at least 90% and 80%, respectively. In vitro, TPT sulfonate is inactive against the parasite suggesting a pro-drug mechanism of action. In mice, TPT sulfonate is fully absorbed and subject to rapid, non-CYP-mediated, first-pass metabolism that is initiated by desulfation and yields a series of metabolites. The initially-formed free thiol-containing metabolite, termed TP thiol, was chemically synthesized; it dose-dependently decreased S. mansoni and Schistosoma haematobium motility in vitro. Also, when administered as a single 50?mg/kg IP dose, TP thiol decreased 33-day-old S. mansoni female and male burdens by 35% and 44%, with less severe organomegaly. Overall, TPT sulfonate's efficacy profile is competitive with that of PZQ. Also, the characterization of a parasiticidal metabolite facilitates an understanding and improvement of the chemistry, and identification of the mechanism of action and/or target.

SUBMITTER: Wolfe AR

PROVIDER: S-EPMC6287543 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling.

Wolfe Alan R AR Neitz R Jeffrey RJ Burlingame Mark M Suzuki Brian M BM Lim K C KC Scheideler Mark M Nelson David L DL Benet Leslie Z LZ Caffrey Conor R CR

International journal for parasitology. Drugs and drug resistance 20181120 3

Treatment of schistosomiasis relies precariously on just one drug, praziquantel (PZQ). In the search for alternatives, 15 S-[2-(alkylamino)alkane] thiosulfuric acids were obtained from a previous research program and profiled in mice for efficacy against both mature (>42-day-old) and juvenile (21-day-old) Schistosoma mansoni using a screening dose of 100 mg/kg PO QDx4. One compound, S-[2-(tert-butylamino)-1-phenylethane] thiosulfuric acid (TPT sulfonate), was the most effective by decreasing fem ...[more]

PMID: 30503203

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Project description:ObjectivesThe single- and multiple-dose pharmacokinetics (PK) of tedizolid were examined after oral administration of tedizolid phosphate disodium (TPD), including the effect of food on PK. The relative bioavailability of TPD to the free acid tedizolid phosphate was determined to bridge the results of these and other studies to the solid form of the prodrug selected for further development.DesignRandomized placebo-controlled, double-blind single- and multiple-ascending dose studies and randomized open-label, crossover food effect and relative bioavailability studies.SettingClinical Research Units.ParticipantsHealthy subjects.InterventionStudy TR701-101 enrolled 40 subjects in single-ascending dose (200-1200 mg TPD or placebo) and 40 subjects in 21-day multiple-ascending dose (200, 300, or 400 mg TPD once/day; 600 mg linezolid twice/day; or placebo) arms. Study TR701-103 was a food-effect study in 12 subjects administered 600 mg TPD. Study TR701-108 was a relative bioavailability study in 12 subjects administered 150-mg tedizolid equivalents as TPD or tedizolid phosphate.Measurements and main resultsPlasma concentrations of the prodrug tedizolid phosphate, its active moiety tedizolid, and/or linezolid were collected. After administration of 200 to 600 mg TPD, tedizolid values increased approximately dose proportionally in area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ). Tedizolid half-life values were approximately 2-fold greater compared with linezolid. TPD administration with food delayed tedizolid absorption and reduced Cmax relative to the fasted state but did not alter AUC. Minimal accumulation was predicted and observed for tedizolid, whereas observed accumulation of linezolid exceeded predictions based on single-dose PK. Comparable PK of tedizolid was observed following oral administration of either TPD or tedizolid phosphate. In the multiple-ascending dose study, 3 of 24 tedizolid subjects were withdrawn under prespecified stopping rules (one each of elevated alanine aminotransferase, low reticulocyte count, or low white blood cell count), as was 1 of 8 linezolid subjects (low reticulocyte count).ConclusionsOverall, tedizolid has a favorable PK profile, a half-life that supports once daily administration, and no nonlinearities at steady state. Tedizolid phosphate can be administered without regard to food.

Dataset Information

TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling.

Publications

TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling.

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