Synthesis and detection of toltrazuril sulfone and its pharmacokinetics in horses following administration in dimethylsulfoxide.

Dirikolu, L., Karpiesiuk, W., Lehner, A. F., Hughes, C., Granstrom, D. E., Tobin,T. Synthesis and detection of toltrazuril sulfone and its pharmacokinetics inhorses following administration in dimethylsulfoxide. J. vet. Pharmacol. Therap.32, 368–378.Triazine-based antiprotozoal agents are known for their lipophylic characte-ristics and may therefore be expected to be well absorbed following oralincreases the absorption of chemicals, extremely lipid-soluble chemicals maydissolve poorly in gastrointestinal (GI) fluids, and their corresponding absorptionand bioavailability would be low. Also, if the compound is administered in solidform and is relatively insoluble in GI fluids, it is likely to have limited contact withthe GI mucosa, and therefore, its rate of absorption will be low. Based on the aboveconsiderations, we sought a solvent with low or no toxicity that would maintaintriazine agents in solution. As the oral route is most preferred for daily drugtherapy, such a solvent would allow an increased rate of absorption following oraladministration. In present study, it was demonstrated that dimethylsulfoxide(DMSO) increased the oral bioavailability of toltrazuril sulfone (Ponazuril)threefold, relative to oral administrations of toltrazuril sulfone suspended inwater. The cross-over study of toltrazuril sulfone formulated in DMSO indicatedthat the absolute oral bioavailability of toltrazuril sulfone in DMSO is 71%. Thehigh bioavailability of the DMSO-preparation suggests that its daily oraladministration will routinely yield effective plasma and cerebral spinal fluid(CSF) concentrations in all horses treated. Also, this improved formulation wouldallow clinicians to administer loading doses of toltrazuril sulfone in acute cases ofEquine Protozoal Myeloencephalitis. Another option would involve administra-tion of toltrazuril sulfone in DMSO mixed with feed (1.23 kg daily dose) meetingthe US Food and Drug Administration (FDA) recommendations for the levels ofDMSO permissible in pharmaceutical preparations.(Paper received 3 November 2008; accepted for publication 3 December 2008)Levent Dirikolu, Department of Veterinary Biosciences, College of Veterinary Medi-cine, University of Illinois, 2001 South Lincoln Avenue, Urbana, IL 61802, USA.E-mail: dirikolu@uiuc.eduThis research was supported by grants from the New Ace Research Companyand Fellowship program from the Ministry of National Education of Turkey.