Theoretical considerations in the calculation of bioavailability of drugs exhibiting Michaelis-Menten elimination kinetics

Two approaches used for bioavailability determination of drugs with Michaelis-Menten elimination kinetics were examined by computer simulation. The first method involved treating the drug as though its clearance remained constant during elimination, and the conventional method of taking the ratio of areas under the curve resulting from the oral and intravenous doses was used to calculate bioavailability. The second approach involved using the Michaelis parameters, Vmax and Km, to determine concentration dependent clearance values, but based these calculations on peripheral drug concentrations rather than on concentrations entering or in the liver. We have developed a simulation method that was used to test the accuracy of the above two methods. In the simulations described, Vmax, Km, and hepatic blood flow were chosen to represent a drug with an extraction ratio of 0.9 under linear conditions, but with Michaelis-Menten kinetics occurring at the doses given. Absorption was assumed to be first-order, and metabolism was assumed to occur only in the liver. These simulations showed that the most accurate determination of bioavailability requires knowledge of the direct contribution of oral absorption to the concentration of drug entering the liver. Unexpectedly, the results also showed that if a drug has a large volume of distribution or a large absorption rate constant, or both, use of the much simpler conventional method of bioavailability determination may be appropriate even in cases where the degree of saturation is substantial.