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The influence of route of administration on the absolute bioavailability and GI tract absorption of nitrofurantoin was investigated in rabbits. The disposition of nitrofurantoin was described by a one-compartment model with simultaneous first-order and Michaelis-Menten type elimination kinetics, and bioavailability was estimated by nonlinear assessment. The plasma levels following oral administration were significantly lower than those after intravenous administration, and absolute F values for oral administration were approximately 0.3. However, F values following intraduodenal administration and portal vein infusion were nearly unity, and it was concluded that the reduction of bioavailability following oral administration could not be attributed to metabolism by intestinal microflora or to the hepatic first-pass effect. Thus, reduction of F values following oral administration is probably due to gastric degradation of the drug. The effects of factors influencing bioavailability, such as water volume taken with the drug, change of gastric emptying rate and effect of particle size, were also investigated. Increase of volume of water administered tended to improve the bioavailability, and a particle size dependency was also observed.

A linear pharmacokinetic model was developed in order to calculate separately the plasma (or blood) concentrations of CM6913 and CM7116, major metabolites of ethyl loflazepate (CM6912), from the total concentrations of CM6913 and CM7116 (CM6913+ CM7116) after the oral administration of CM6912 to dogs and humans.The plasma (or blood) concentrations of CM6913 and CM7116 were elaborately determined by the addition of alkaline solution to inhibit CM6913 degradation.The CM6913 concentration was well simulated by this calculation except for the deviation from one-compartment model in later time after the administration to dogs. The calculated CM7116 concentration was also comparable to the observed concentration.In an early period after the administration, however, the plasma (or blood) concentration of CM7116 was underestimated, especially in humans.The total plasma concentrations of CM6913 and CM7116 are measured routinely because of the rapid degradation of CM6913 in biological samples, hence this model approach will be useful for the separate estimation of the concentrations of the metabolites.In humans, the elimination half-life of CM7116, the most active metabolite of CM6912, was long (132h), which suggests the prolonged effects of CM6912.

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