A Pharmacokinetic Basis for the Efficacy of 4-Amino-6-Trichloroethenyl-1,3-Benzenedisulfonamide against Fasciola hepatica in the Rat

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Abstract
The pharmacokinetic basis for the efficacy of 4-amino-6-trichloroethenyl-1,3-benzenedisulfonamide (L-631,529) against mature F. hepatica was studied in experimentally infected rats. Single oral doses of the sulfonamide of 12.5-100 mg/kg were 84-100% effective against 16-20 wk old infections. Efficacy decreased below 12.5 mg/kg as the drug displayed only moderate activity at 6.25 mg/kg. Pharmacokinetic studies using 14C-labeled sulfonamide at 6.25 and 12.5 mg/kg showed that the drug rapidly entered the blood, attained a maximum concentration approximately 4 h after dosing and then decreased exponentially. Approximately 75% of the circulating drug was in the plasma and the remainder was in the erythrocytes. Drug levels in F. hepatica paralleled those in the blood after a lag in time. Drug concentration in the flukes rose rapidly, peaked 8-12 h post-administration and decayed exponentially. Gross observations indicated that onset of drug clearance from the flukes appeared to coincide with cessation of feeding by the parasites. The sulfonamide was a potent inhibitor of rat erythrocyte carbonic anhydrase and virtually complete inhibition occurred 5-8 h after treatment at 6.25 and 12.5 mg/kg. The inhibition of carbonic anhydrase activity then decreased in parallel with the drug level in the erythrocytes. Calculations indicated that binding of the sulfonamide to carbonic anhydrase in a 1:1 stoichiometry can account for 70-100% of the drug in the erythrocytes. I.v. administration i.v. of 14C-labeled L-631,529 absorbed onto rat red blood cells demonstrated that bound drug was directly incorporated into the parasites. The drug did not disassociate from the red cells into the plasma. The sulfonamide probably reaches the liver flukes via a mechanism which in part involves ingestion of the red cells containing the drug bound to the carbonic anhydrase.

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