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Methyl-N[5 [[4-(2-pyridinyl)-1-piperazinyl]carbonyl]- 1H-benzimidazol-2-yl] carbamate (CDRI-81/470) is a broad spectrum anthelmintic agent, effective against both intestinal and systemic parasitism. Tissue distribution and excretion of CDR1-81/470 were studied in rats after a single oral dose of 100 mg kg(-1) CDRI-81/470. One of the metabolites was identified in pilot studies as its N-decarboxylate derivative and characterized by synthesis. HPLC assay methods for the simultaneous estimation of CDRI-81/470 and its N-decarboxylate derivative in tissues, bile, urine, and faeces were developed and validated. The parent compound was quantitated in all major tissues and organs up to 48 h post-dose. Among the tissues other than serum, the highest concentrations of CDRI-81/470 were found in liver, whereas only trace levels were found in brain. Approximately 3% of the administered dose was excreted unchanged in urine at 120 h postdose, whereas approximately 7% was recovered in faeces. The contribution of the biliary route for the excretion of parent compound was less than 0.5%. The N-decarboxylate derivative was quantitated in faeces (1-4%) and bile ( < 0.1%) but was absent in serum, tissues, and urine. An additional metabolite was isolated from bile and characterized as the pyridinyl-5-hydroxy derivative of CDRI-81/470. CDRI-81/470 showed rapid absorption and distribution into all major organs and tissues, and underwent extensive metabolism in rats. Two metabolites in bile were identified and characterized by synthesis.

Data transformations and weighting schemes are normally used to obtain the best-fit of standard curves in bioanalysis and the calibration model is usually selected during prevalidation. In the present study, a comparison has been made between unweighted and weighted (1/x, 1/x2, and 1/square root of x) regression models with or without an intercept in achieving the best-fit for the standard curve of CDRI compound 81/470, a new anthelmintic agent, in cow milk. Validation samples in milk at the LLOQ, medium, and high concentrations were also analysed by each of the calibration models. An unweighted regression equation with an intercept overestimated the concentrations at the LLOQ. An unweighted equation without intercept and weighted equations with or without an intercept significantly minimized the bias at the LLOQ without distorting the results at higher concentrations. Hence, an unweighted equation for a straight line passing through the origin was found to be the best model for a standard curve of 81/470 in milk. Similar results were obtained for 81/470 and UMF-078 in serum and plasma, respectively. Bioanalysts should routinely test these models to obtain the best fit model for their calibration curves as part of their assay validation not during prevalidation.

CDRI compound 81/470 (AH) is a new broad-spectrum anthelminthic agent under development for clinical and veterinary application. We herewith report the synthesis of 14C-labelled AH, and a study of the tissue distribution and excretion of radioactivity after administering a single 1 mg/kg p.o. or i.v. dose in young male rats. After oral administration of the dose, percent radioactivity recovered in 24-h urine, faeces and tissues were 17.9, 59.7 and 22.9 respectively. The levels were below detection limit in brain and gonads up to 24 h. In bile-duct-cannulated rats, the majority (37.8 +/- 2.8 and 43.8 +/- 6.4) of the radioactivity was excreted in the bile within 24 h of p.o. and i.v. administration, respectively. After an oral dose (1 mg/kg), the urinary excretion of radioactivity in rats was found to be approximately one-half (21 +/- 5.7, 18.3 +/- 2.1) of that obtained by i.v. administration of an equal dose (40.2 +/- 3.1 and 35 +/- 1.3), in bile-duct-intact and cannulated rats respectively.